Bicyclic heterocycles as fgfr inhibitors

ABSTRACT

The present invention relates to bicyclic heterocycles, and pharmaceutical compositions of the same, that are inhibitors of the FGFR3 enzyme and are useful in the treatment of FGFR3-associated diseases such as cancer.

FIELD OF THE INVENTION

The present disclosure relates to bicyclic heterocycles, andpharmaceutical compositions of the same, that are inhibitors of theenzyme FGFR3 and are useful in the treatment of FGFR3-associateddiseases such as cancer.

BACKGROUND OF INVENTION

The Fibroblast Growth Factor Receptors (FGFR) are receptor tyrosinekinases that bind to fibroblast growth factor (FGF) ligands. There arefour FGFR proteins (FGFR1-4) that are capable of binding ligands and areinvolved in the regulation of many physiological processes includingtissue development, angiogenesis, wound healing, and metabolicregulation. Upon ligand binding, the receptors undergo dimerization andphosphorylation leading to stimulation of the protein kinase activityand recruitment of many intracellular docking proteins. Theseinteractions facilitate the activation of an array of intracellularsignaling pathways including Ras-MAPK, AKT-PI3K, and phospholipase Cthat are important for cellular growth, proliferation and survival(Reviewed in Eswarakumar et al. Cytokine & Growth Factor Reviews, 2005).

Aberrant activation of this pathway either through overexpression of FGFligands or FGFR or activating mutations in the FGFRs can lead to tumordevelopment, progression, and resistance to conventional cancertherapies. In human cancer, genetic alterations including geneamplification, chromosomal translocations and somatic mutations thatlead to ligand-independent receptor activation have been described.Large scale DNA sequencing of thousands of tumor samples has revealedthat components of the FGFR pathway are among the most frequentlymutated in human cancer. Many of these activating mutations areidentical to germline mutations that lead to skeletal dysplasiasyndromes. Mechanisms that lead to aberrant ligand-dependent signalingin human disease include overexpression of FGFs and changes in FGFRsplicing that lead to receptors with more promiscuous ligand bindingabilities (Reviewed in Knights and Cook Pharmacology & Therapeutics,2010; Turner and Grose, Nature Reviews Cancer, 2010). Therefore,development of inhibitors targeting FGFR may be useful in the clinicaltreatment of diseases that have elevated FGF or FGFR activity.

The cancer types in which FGF/FGFRs are implicated include, but are notlimited to: carcinomas (e.g., bladder, breast, cervical, colorectal,endometrial, gastric, head and neck, kidney, liver, lung, ovarian,prostate); hematopoietic malignancies (e.g., multiple myeloma, chroniclymphocytic lymphoma, adult T cell leukemia, acute myelogenous leukemia,non-Hodgkin lymphoma, myeloproliferative neoplasms, and Waldenstrom'sMacroglubulinemia); and other neoplasms (e.g., glioblastoma, melanoma,and rhabdosarcoma). In addition to a role in oncogenic neoplasms, FGFRactivation has also been implicated in skeletal and chondrocytedisorders including, but not limited to, achrondroplasia andcraniosynostosis syndromes.

There is a continuing need for the development of new drugs for thetreatment of cancer, and the FGFR3 inhibitors described herein helpaddress this need.

SUMMARY OF INVENTION

The present disclosure is directed to compounds having Formula (I):

or pharmaceutically acceptable salts thereof, wherein constituentvariables are defined herein.

The present disclosure is further directed to pharmaceuticalcompositions comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier.

The present disclosure is further directed to methods of inhibiting anFGFR3 enzyme comprising contacting the enzyme with a compound of Formula(I), or a pharmaceutically acceptable salt thereof.

The present disclosure is further directed to a method of treating adisease associated with abnormal activity or expression of an FGFR3enzyme, comprising administering a compound of Formula (I), or apharmaceutically acceptable salt thereof, to a patient in need thereof.

The present disclosure is further directed to compounds of Formula (I)for use in treating a disease associated with abnormal activity orexpression of an FGFR3 enzyme.

The present disclosure is further directed to a method for treating adisorder mediated by an FGFR3 enzyme, or a mutant thereof, in a patientin need thereof, comprising the step of administering to said patient acompound of Formula (I), or pharmaceutically acceptable compositionthereof.

The present disclosure is further directed to a method for treating adisorder mediated by an FGFR3 enzyme, or a mutant thereof, in a patientin need thereof, comprising the step of administering to the patient acompound of Formula (I), or a pharmaceutically acceptable salt thereof,or a composition comprising a compound of Formula (I), or apharmaceutically acceptable salt thereof, in combination with anothertherapy or therapeutic agent as described herein.

The present disclosure is further directed to the use of compounds ofFormula (I) in the preparation of a medicament for use in therapy.

DETAILED DESCRIPTION Compounds

In one aspect, the present disclosure provides compounds of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

Cy¹ is selected from C₆₋₁₀ aryl and 5-10 membered heteroaryl; whereineach 5-10 membered heteroaryl has at least one ring-forming carbon atomand 1, 2, 3, or 4 ring-forming heteroatoms independently selected fromN, O, and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of 5-10 membered heteroaryl is optionallysubstituted by oxo to form a carbonyl group; and wherein the C₆₋₁₀ aryland 5-10 membered heteroaryl are each optionally substituted with 1, 2,3 or 4 substituents independently selected from R¹⁰;

Cy^(A) is selected from C₃₋₁₂ cycloalkyl and 4-12 memberedheterocycloalkyl; wherein each 4-12 membered heterocycloalkyl has atleast one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms independently selected from N, O, and S; wherein the N and Sare optionally oxidized; wherein a ring-forming carbon atom of 4-12membered heterocycloalkyl is optionally substituted by oxo to form acarbonyl group; wherein when the C₃₋₁₂ cycloalkyl and 4-12 memberedheterocycloalkyl of Cy^(A) has a fused aromatic ring attached thereto,the C₃₋₁₂ cycloalkyl and 4-12 membered heterocycloalkyl is directlyattached to the pyrazolopyridine core structure through a ring-formingatom of the saturated or partially saturated ring; and wherein the C₃₋₁₂cycloalkyl and 4-12 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR²⁰;

R¹ is selected from H, D, halo, CN, C₁₋₆ alkyl, OR^(a) and NR^(c)R^(d);wherein the C₁₋₆ alkyl is optionally substituted with 1, 2, or 3substituents independently selected from R^(g);

R² is selected from H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, CN, SR^(a7), C(O)R^(b7),C(O)NR^(c7)R^(d7), C(O)OR^(a7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)OR^(a7), NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7),NR^(c7)S(O)₂NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7),and S(O)₂NR^(c7)R^(d7); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R³⁰;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1),C(═NR^(e1))R^(b1), C(═NOR^(a1))R^(b1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), andS(O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkenyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), (O)OR^(a3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²;

each R¹² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a5),SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5), NR^(c5)S(O)R^(b5),NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl and 4-7 membered heterocycloalkyl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R²⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2),NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2),C(═NR^(e2))R^(b2), C(═NOR^(a2))R^(b2), C(=NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R_(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2),and S(O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R²¹;

or two adjacent R²⁰ substituents on the Cy^(A) ring, taken together withthe atoms to which they are attached, form a fused 5- or 6-memberedheteroaryl ring, or a fused phenyl ring; wherein each fused 5- or6-membered heteroaryl ring has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein a ring-forming carbon atom of each fused 5- or 6-memberedheteroaryl ring is optionally substituted by oxo to form a carbonylgroup; and wherein the fused 5- or 6-membered heteroaryl ring, and fusedphenyl ring are each optionally substituted with 1, 2, 3 or 4substituents independently selected from R²¹;

each R²¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),NR^(c4)R^(d4), NR^(c4)C(O)OR^(a4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²²;

or two R²¹ substituents taken together with the carbon atom to whichthey are attached form a spiro 3-7-membered heterocycloalkyl ring, or aspiro C₃₋₆ cycloalkyl ring; wherein each spiro 3-7-memberedheterocycloalkyl ring has at least one ring-forming carbon atom and 1, 2or 3 ring-forming heteroatoms independently selected from N, O, and S;wherein a ring-forming carbon atom of each spiro 3-7-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the spiro 3-7membered heterocycloalkyl ringand spiro C₃₋₆ cycloalkyl ring are each optionally substituted with 1,2, 3 or 4 substituents independently selected from R²²;

each R²² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a6),SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6), NR^(c6)S(O)R^(b6),NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R³⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a8),SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), NR^(c8)R^(d8),NR^(c8)C(O)R^(b8), NR^(c8)C(O)OR^(a8), NR^(c8)S(O)R^(b8),NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), S(O)R^(b8),S(O)NR^(c8)R^(d8), S(O)₂R^(b8), and S(O)₂NR^(c8)R^(d8); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R^(a), R^(c) and R^(d) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl,are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹;

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹;

each R^(e1) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkyl sulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(a2), R^(c2) and R^(d2), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²¹;

or any R^(c2) and R^(d2) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R²¹;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²¹;

each R^(e2) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkyl sulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(a3), R^(c3) and R^(d3), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²;

or any R^(c3) and R^(d3) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R¹²;

each R^(b3) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkylC₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl, are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹²;

each R^(a4), R^(c4) and R^(d4), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²²;

or any R^(c4) and R^(d4) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R²²;

each R^(b4) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl;

wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²²;

each R^(a5), R^(c5) and R^(d5), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

or any R^(c5) and R^(d5) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(b5) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a6), R^(c6) and R^(d6), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b6) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a7), R^(c7), and R^(d7) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl,are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R³⁰;

or any R^(c7) and R^(d7) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R³⁰;

each R^(b7) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R³⁰;

each R^(a8), R^(c8) and R^(d8), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g);

or any R^(c8) and R^(d8) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R^(g);

each R^(b8) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkylC₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g); and

each Rg is independently selected from OH, NO₂, CN, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl-C₁₋₂ alkylene, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₃ alkoxy-C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkoxy, HO—C₁₋₃ alkoxy, HO—C₁₋₃ alkyl,cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino.

In some embodiments, provided herein is a compound of Formula (I),wherein:

Cy¹ is selected from:

-   -   (i) C₆₋₁₀ aryl,    -   (ii) monocyclic 5-6 membered heteroaryl, wherein each monocyclic        5-6 membered heteroaryl has at least one ring-forming carbon        atom and 1, 2, 3, or 4 ring-forming heteroatoms independently        selected from N, O, and S; and    -   (iii) bicyclic 8-10 membered heteroaryl, wherein each bicyclic        8-10 membered heteroaryl has at least one ring-forming carbon        atom, and 1, 2, or 3 ring-forming heteroatoms independently        selected from O and S, and optionally 1, 2 or 3 ring-forming        heteroatoms that are N;

wherein the N and S of the monocyclic 5-6 membered heteroaryl andbicyclic 8-10 membered heteroaryl of Cy¹ are optionally oxidized; aring-forming carbon atom of monocyclic 5-6 membered heteroaryl andbicyclic 8-10 membered heteroaryl of Cy¹ is optionally substituted byoxo to form a carbonyl group; and the C₆₋₁₀ aryl, monocyclic 5-6membered heteroaryl, and bicyclic 8-10 membered heteroaryl of Cy¹ areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹⁰;

Cy^(A) is selected from C₃₋₁₂ cycloalkyl and 4-12 memberedheterocycloalkyl; wherein each 4-12 membered heterocycloalkyl has atleast one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms independently selected from N, O, and S; wherein the N and Sare optionally oxidized; wherein a ring-forming carbon atom of 4-12membered heterocycloalkyl is optionally substituted by oxo to form acarbonyl group; wherein when the C₃₋₁₂ cycloalkyl and 4-12 memberedheterocycloalkyl of Cy^(A) has a fused aromatic ring attached thereto,the C₃₋₁₂ cycloalkyl and 4-12 membered heterocycloalkyl is directlyattached to the pyrazolopyridine core structure through a ring-formingatom of the saturated or partially saturated ring; and wherein the C₃₋₁₂cycloalkyl and 4-12 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR²⁰;

R¹ is selected from H, D, halo, CN, C₁₋₆ alkyl, OR^(a) and NR^(c)R^(d);wherein the C₁₋₆ alkyl is optionally substituted with 1, 2, or 3substituents independently selected from R^(g);

R² is selected from H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, CN, OR^(a7), SR^(a7), (O)R^(b7),C(O)NR^(c7)R^(d7), C(O)OR^(a7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)OR^(a7), NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7),NR^(c7)S(O)₂NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7),and S(O)₂NR^(c7)R^(d7); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R³⁰;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1),C(═NR^(e1))R^(b1), C(═NOR^(a1))R^(b1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR_(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),and S(O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3)S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²;

each R¹² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a5),SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5), NR^(c5)S(O)R^(b5),NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl and 4-7 membered heterocycloalkyl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R²⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2),NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2),C(═NR^(e2))R^(b2), C(=NOR^(a2))R^(b2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R²¹;

or two adjacent R²⁰ substituents on the Cy^(A) ring, taken together withthe atoms to which they are attached, form a fused 5- or 6-memberedheteroaryl ring, or a fused phenyl ring; wherein each fused 5- or6-membered heteroaryl ring has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein a ring-forming carbon atom of each fused 5- or 6-memberedheteroaryl ring is optionally substituted by oxo to form a carbonylgroup; and wherein the fused 5- or 6-membered heteroaryl ring, and fusedphenyl ring are each optionally substituted with 1, 2, 3 or 4substituents independently selected from R²¹;

each R²¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),NR^(c4)R^(d4), NR^(c4)C(O)R^(b4) NR^(c4)C(O)OR^(a4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²²;

or two R²¹ substituents taken together with the carbon atom to whichthey are attached form a spiro 3-7-membered heterocycloalkyl ring, or aspiro C₃₋₆ cycloalkyl ring; wherein each spiro 3-7-memberedheterocycloalkyl ring has at least one ring-forming carbon atom and 1, 2or 3 ring-forming heteroatoms independently selected from N, O, and S;wherein a ring-forming carbon atom of each spiro 3-7-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the spiro 3-7membered heterocycloalkyl ringand spiro C₃₋₆ cycloalkyl ring are each optionally substituted with 1,2, 3 or 4 substituents independently selected from R²²;

each R²² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a6),SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6), NR^(c6)S(O)R^(b6),NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R³⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a8),SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), NR^(c8)R^(d8),NR^(c8)C(O)R^(b8), NR^(c8)C(O)OR^(a8), NR^(c8)S(O)R^(b8),NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), S(O)R^(b8),S(O)NR_(c8)R^(d8), S(O)₂R^(b8), and S(O)₂NR^(c8)R^(d8); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R^(a), R^(c) and R^(d) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl,are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹;

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹;

each R^(e1) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkyl sulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl,aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆ alkyl)aminosulfonyl;

each R^(a2), R^(c2) and R^(d2), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²¹;

or any R^(c2) and R^(d2) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R²¹;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²¹;

each R^(e2) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkyl sulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(a3), R^(c3) and R^(d3), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²;

or any R^(c3) and R^(d3) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R¹²;

each R^(b3) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkylC₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl, are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹²;

each R^(a4), R^(c4) and R^(d4), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²²;

or any R^(c4) and R^(d4) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R²²;

each R^(b4) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkylC₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR²²;

each R^(a5), R^(c5) and R^(d5), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

or any R^(c5) and R^(d5) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(b5) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a6), R^(c6) and R^(d6), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b6) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a7), R^(c7), and R^(d7) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl,are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R³⁰;

or any R^(c7) and R^(d7) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R³⁰;

each R^(b7) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R³⁰;

each R^(a8), R^(c8) and R^(d8), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g);

or any R^(c8) and R^(d8) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R^(g);

each R^(b8) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkylC₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g); and

each R^(g) is independently selected from OH, NO₂, CN, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl-C₁₋₂ alkylene, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₃ alkoxy-C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkoxy, HO—C₁₋₃ alkoxy, HO—C₁₋₃ alkyl,cyano-C₁₋₃ alkyl, H2N-C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino.

In some embodiments, Cy¹ is selected from monocyclic C₆₋₁₀ aryl andmonocyclic 5-6 membered heteroaryl; wherein each monocyclic 5-6 memberedheteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4ring-forming heteroatoms independently selected from N, O, and S;wherein the N and S are optionally oxidized; wherein a ring-formingcarbon atom of the monocyclic 5-6 membered heteroaryl is optionallysubstituted by oxo to form a carbonyl group; and wherein the monocyclicC₆₋₁₀ aryl and monocyclic 5-6 membered heteroaryl are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR^(io)

In some embodiments, Cy¹ is selected from phenyl and monocyclic 5-6membered heteroaryl having at least one ring-forming carbon atom and 1,2, 3 or 4 ring-forming nitrogen atoms; wherein the phenyl and monocyclic5-6 membered heteroaryl are each optionally substituted with 1, 2, 3 or4 substituents independently selected from R¹⁰.

In some embodiments, Cy¹ is a monocyclic 5-6 membered heteroaryl havingat least one ring-forming carbon atom and 1, 2, 3 or 4 ring-formingnitrogen atoms, optionally substituted with 1, 2, 3 or 4 substituentsindependently selected from R¹⁰.

In some embodiments, Cy¹ is selected from thienopyridinyl, pyrazolyl,triazolyl and phenyl; wherein thienopyridinyl, pyrazolyl, triazolyl andphenyl are each optionally substituted with 1, 2, 3 or 4 substituentsindependently selected from R¹⁰. In some embodiments, Cy¹ is pyrazolyloptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹⁰. In some embodiments, Cy¹ is triazolyl optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR¹⁰. In some embodiments, Cy¹ is phenyl optionally substituted with 1,2, 3 or 4 substituents independently selected from R¹⁰. In someembodiments, Cy¹ is thienopyridinyl optionally substituted with 1, 2, 3or 4 substituents independently selected from R¹⁰.

In some embodiments, Cy¹ is selected from 1-methyl-1H-pyrazol-4-yl,1-methyl-1H-1,2,3-triazol-4-yl, 1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl,1-(2-morpholinoethyl)-1H-pyrazol-4-yl,3-fluoro-4-(4-methylpiperazin-1-yl)phenyl, andthieno[3,2-c]pyridin-2-yl.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1), and NR^(c1)R^(d1), whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, halo,D, CN, OR^(a1), C(O)NR^(c1)R^(d1) and NR^(c1)R^(d1); wherein said C₁₋₆alkyl, C₃₋₁₀ cycloalkyl and 4-10 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, and halo; wherein saidC₁₋₆ alkyl, C₃₋₁₀ cycloalkyl and 4-10 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,4-10 membered heterocycloalkyl, and halo; wherein said C₁₋₆ alkyl and4-10 membered heterocycloalkyl are each optionally substituted with 1,2, 3, or 4 substituents independently selected from R¹¹. In someembodiments, R¹⁰ is C₁₋₆ alkyl optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹. In some embodiments, R¹⁰is 4-10 membered heterocycloalkyl optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹¹. In some embodiments,R¹⁰ is halo. In some embodiments, R¹⁰ is fluoro, chloro, or bromo. Insome embodiments, wherein R¹⁰ is fluoro.

In some embodiments, each R¹⁰ is independently selected from methyl,4-methylpiperazin-1-yl, 2-morpholinoethyl, pyridin-3-ylmethyl andfluoro. In some embodiments, wherein each R¹⁰ is methyl.

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), andNR^(c3)R^(d3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹².

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, halo, D, CN, OR^(a3), SR^(a3), andNR^(c3)R^(d3); wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹².

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, halo, D, CN, OR^(a3) and NR^(c3)R^(d3); wherein said C₁₋₆alkyl, 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹².

In some embodiments, each R¹¹ is independently selected from 4-10membered heterocycloalkyl, and 5-10 membered heteroaryl. In someembodiments, R¹¹ is 4-10 membered heterocycloalkyl. In some embodiments,R¹¹ is 5-6 membered heterocycloalkyl. In some embodiments, R¹¹ is 5-10membered heteroaryl. In some embodiments, wherein R¹¹ is 5-6 memberedheteroaryl. In some embodiments, each R¹¹ is independently selected from2-morpholino and pyridin-3-yl.

In some embodiments, Cy^(A) is 4-12 membered heterocycloalkyl; whereinthe 4-12 membered heterocycloalkyl has at least one ring-forming carbonatom and 1, 2, 3, or 4 ring-forming heteroatoms independently selectedfrom N, O, and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of 4-12 membered heterocycloalkyl is optionallysubstituted by oxo to form a carbonyl group; and wherein the 4-12membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4substituents independently selected from R²⁰.

In some embodiments, Cy^(A) is 5-8 membered heterocycloalkyl; whereinthe 5-8 membered heterocycloalkyl has at least one ring-forming carbonatom and 1, 2 or 3 ring-forming heteroatoms independently selected fromN, O, and S; wherein a ring-forming carbon atom of 5-8 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the 5-8 membered heterocycloalkyl is optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR²⁰.

In some embodiments, Cy^(A) is 6 membered heterocycloalkyl; wherein the6 membered heterocycloalkyl has at least one ring-forming carbon atomand 1 or 2 ring-forming heteroatoms independently selected from N, O,and S; wherein a ring-forming carbon atom of 6 membered heterocycloalkylis optionally substituted by oxo to form a carbonyl group; and whereinthe 6 membered heterocycloalkyl is optionally substituted with 1, 2, 3or 4 substituents independently selected from R²⁰.

In some embodiments, Cy^(A) is 6-membered heterocycloalkyl selected frompiperazinyl, piperidinyl, 5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl and6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl; wherein a ring-formingcarbon atom of the 6-membered heterocycloalkyl is optionally substitutedby oxo to form a carbonyl group; and wherein the 6 memberedheterocycloalkyl is optionally substituted with 1, 2, 3 or 4substituents independently selected from R²⁰.

In some embodiments, Cy^(A) is piperazinyl; wherein a ring-formingcarbon atom of piperazinyl is optionally substituted by oxo to form acarbonyl group; and the piperazinyl is optionally substituted with 1, 2,3 or 4 substituents independently selected from R²⁰.

In some embodiments, Cy^(A) is piperidinyl; wherein a ring-formingcarbon atom of piperidinyl is optionally substituted by oxo to form acarbonyl group; and the piperidinyl is optionally substituted with 1, 2,3 or 4 substituents independently selected from R²⁰.

In some embodiments, Cy^(A) is 4-methyl-3-oxopiperazin-1-yl optionallysubstituted with 1, 2, or 3 substituents independently selected fromR²⁰.

In some embodiments, Cy^(A) is 4-12 membered heterocycloalkyl optionallysubstituted with 1, 2, or 3 substituents independently selected fromR²⁰; wherein the 4-12 membered heterocycloalkyl has at least onering-forming carbon atom and 1, 2 or 3 ring-forming heteroatomsindependently selected from N, O, and S; wherein at least one of thering-forming heteroatoms is N and wherein the 4-12 memberedheterocycloalkyl is attached to the pyrazolopyridine core structurethrough a ring forming nitrogen atom.

In some embodiments, Cy^(A) is 4-12 membered heterocycloalkyl, wherein aring-forming carbon atom of the 4-12 membered heterocycloalkyl issubstituted by oxo to form a carbonyl group.

In some embodiments, Cy^(A) is selected from 3-hydroxypiperidin-1-yl,6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl,1-(trifluoromethyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl,3-methyl-2-oxo-3,8-diazabicyclo[3.2.1]octan-8-yl,2-isopropyl-4-methyl-3-oxopiperazin-1-yl,2-ethyl-4-methyl-3-oxopiperazin-1-yl,2,2-diethyl-4-methyl-3-oxopiperazin-1-yl,2-benzyl-4-methyl-3-oxopiperazin-1-yl,2-(cyclopropylmethyl)-4-methyl-3-oxopiperazin-1-yl,4-methyl-3-oxo-2-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl,4-methyl-3-oxo-2-(pyridin-4-ylmethyl)piperazin-1-yl,4-methyl-3-oxo-2-(1-phenylethyl)piperazin-1-yl,2-cyclopropyl-4-methyl-3-oxopiperazin-1-yl,4-cyclopropyl-2-methyl-3-oxopiperazin-1-yl, and2,4,5-trimethyl-3-oxopiperazin-1-yl.

In some embodiments, each R²⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, halo,D, CN, OR^(a2), C(O)NR^(c2)R^(d2) and NR^(c2)R^(d2); wherein said C₁₋₆alkyl, C₃₋₁₀ cycloalkyl and 4-10 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²¹;

or two adjacent R²⁰ substituents on the Cy^(A) ring, taken together withthe atoms to which they are attached, form a fused 5- or 6-memberedheteroaryl ring, or a fused phenyl ring; wherein each fused 5- or6-membered heteroaryl ring has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein a ring-forming carbon atom of each fused 5- or 6-memberedheteroaryl ring is optionally substituted by oxo to form a carbonylgroup; and wherein the fused 5- or 6-membered heteroaryl ring, and fusedphenyl ring are each optionally substituted with 1, 2, 3 or 4substituents independently selected from R²¹.

In some embodiments, each R²⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, halo,D, CN, OR^(a2), C(O)NR^(c2)R^(d2) and NR^(c2)R^(d2); wherein said C₁₋₆alkyl, C₃₋₁₀ cycloalkyl and 4-10 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²¹.

In some embodiments, each R²⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, andOR^(a2); wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl and 4-10 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R²¹.

In some embodiments, two adjacent R²⁰ substituents on the Cy^(A) ring,taken together with the atoms to which they are attached, form a fused5- or 6-membered heteroaryl ring, or a fused phenyl ring; wherein eachfused 5- or 6-membered heteroaryl ring has at least one ring-formingcarbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independentlyselected from N, O, and S; wherein a ring-forming carbon atom of eachfused 5- or 6-membered heteroaryl ring is optionally substituted by oxoto form a carbonyl group; and wherein the fused 5- or 6-memberedheteroaryl ring, and fused phenyl ring are each optionally substitutedwith 1, 2, 3 or 4 substituents independently selected from R²¹.

In some embodiments, each R²⁰ is independently selected from OH, methyl,ethyl, isopropyl, cyclopropyl, and tetrahydropyran, each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR²¹;

or two adjacent R²⁰ substituents on the Cy^(A) ring, taken together withthe atoms to which they are attached, form a fused pyrazole orimidazole; each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²¹.

In some embodiments, two adjacent R²⁰ substituents on the Cy^(A) ring,taken together with the atoms to which they are attached, form a fusedbicycle such that Cy^(A) is selected from5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl and6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl; wherein each fused bicycleis optionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²¹. In some embodiments, each R²¹ is independentlyselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo,D, CN, OR^(a4) and NR″R″; wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²².

In some embodiments, each R²¹ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, and5-10 membered heteroaryl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R²². In some embodiments,each R²¹ is independently selected from C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl; wherein said C₃₋₁₀cycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR²².

In some embodiments, each R²¹ is independently selected from C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl.In some embodiments, each R²¹ is C₁₋₆ haloalkyl. In some embodiments,each R²¹ is C₃₋₁₀ cycloalkyl. In some embodiments, each R²¹ is C₆₋₁₀aryl. In some embodiments, each R²¹ is 5-10 membered heteroaryl. In someembodiments, each R²¹ is independently selected from trifluoromethyl,phenyl, pyridine and cyclopropyl.

In some embodiments, each R^(a2), R^(c2) and R^(d2), is independentlyselected from H and C₁₋₆ alkyl. In some embodiments, each R^(a2) is H.

In some embodiments, le is selected from H, D, and C₁₋₆ alkyl. In someembodiments, R¹ is H.

In some embodiments, R² is selected from H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10membered heteroaryl-C₁₋₃ alkylene, halo, CN, OR^(a7), SR^(a7),C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O) R^(a7), NR^(a7)R^(d7),NR^(c7)C(O)R^(b7), NR^(c7)C(O)OR^(a7), NR^(c7)S(O)R^(b7),NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NRc⁷R^(d7), S(O)R^(b7),S(O)NR^(c7)R^(d7), S(O)₂R^(b7), and S(O)₂NR^(c7)R^(d7); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene,4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkyleneand 5-10 membered heteroaryl-C₁₋₃ alkylene are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR³⁰.

In some embodiments, R² is selected from H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,CN, OR^(a7), and NR^(c7)R^(d7); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and5-10 membered heteroaryl-C₁₋₃ alkylene are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R³⁰.

In some embodiments, R² is selected from H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₆₋₁₀ aryl-C₁₋₃ alkylene, halo, CN, OR^(a7), and NR^(c7)R^(d7); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, and C₆₋₁₀ aryl-C₁₋₃ alkylene are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R³⁰. In someembodiments, R² is selected from H, D, C₁₋₆ alkyl, 5-10 memberedheteroaryl, C₆₋₁₀ aryl-C₁₋₃ alkylene, halo, CN and OR^(a7); wherein saidC₁₋₆ alkyl 5-10 membered heteroaryl, and C₆₋₁₀ aryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2 or 3 substituents independentlyselected from R³⁰. In some embodiments, R² is selected from H, methyl,methoxy, chloride, nitrile, furanyl, and benzyl. In some embodiments, R²is H.

In some embodiments, each R³⁰ is independently selected from C₁₋₆ alkyl,C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 memberedheterocycloalkyl; wherein said C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g). In some embodiments, each R³⁰ is independentlyselected from C₁₋₆ alkyl and phenyl. In some embodiments, each R³⁰ isphenyl.

In some embodiments, each R^(a7) is independently selected from H andC₁₋₆ alkyl. In some embodiments, each R^(a7) is methyl.

In some embodiments the compound of Formula I is a compound of FormulaIIa:

or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, 3, or4.

In some embodiments the compound of Formula I is a compound of FormulaIIb:

or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, or 3.

In some embodiments the compound of Formula I is a compound of FormulaIIc:

or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2.

In some embodiments the compound of Formula I is a compound of FormulaIId:

or a pharmaceutically acceptable salt thereof, wherein v is 1, 2, 3 or4.

In some embodiments the compound of Formula I is a compound of FormulaIII:

or a pharmaceutically acceptable salt thereof, wherein q is 1, 2, or 3.

In some embodiments the compound of Formula I is a compound of FormulaIVa:

or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, 3, or4 and q is 1, 2, or 3.

In some embodiments the compound of Formula I is a compound of FormulaIVb:

or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, or 3and wherein q is 1, 2, or 3.

In some embodiments the compound of Formula I is a compound of FormulaIVc:

or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2 andwherein q is 1, 2, or 3.

In some embodiments the compound of Formula I is a compound of FormulaIVd:

or a pharmaceutically acceptable salt thereof, wherein v is 1, 2, 3 or 4and wherein q is 1, 2, or 3.

In some embodiments, provided herein is a compound of Formula (I),wherein:

Cy¹ is selected from monocyclic C₆₋₁₀ aryl and monocyclic 5-6 memberedheteroaryl; wherein each monocyclic 5-6 membered heteroaryl has at leastone ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein the N and S areoptionally oxidized; wherein a ring-forming carbon atom of themonocyclic 5-6 membered heteroaryl is optionally substituted by oxo toform a carbonyl group; and wherein the monocyclic C₆₋₁₀ aryl andmonocyclic 5-6 membered heteroaryl are each optionally substituted with1, 2, 3 or 4 substituents independently selected from R¹⁰;

Cy^(A) is selected from 4-12 membered heterocycloalkyl; wherein the 4-12membered heterocycloalkyl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of 4-12 membered heterocycloalkyl is optionallysubstituted by oxo to form a carbonyl group; and wherein the 4-12membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4substituents independently selected from R²⁰;

R¹ is selected from H, D, halo, CN, C₁₋₆ alkyl, ORa and NR^(c)R^(d);wherein the C₁₋₆ alkyl is optionally substituted with 1, 2, or 3substituents independently selected from R^(g);

R² is selected from H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, CN, and OR^(a7); wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R³⁰;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1), and NR^(c1)R^(d1); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), andNR^(c3)R^(d3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹²;

each R¹² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a5),SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5) andNR^(c5)C(O)R^(b5); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-7 memberedheterocycloalkyl, are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R²⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, halo, D, CN, OR^(a2),C(O)NR^(c2)R^(d2) and NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₃₋₁₀cycloalkyl and 4-10 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR²¹;

or two adjacent R²⁰ substituents on the Cy^(A) ring, taken together withthe atoms to which they are attached, form a fused 5- or 6-memberedheteroaryl ring, or a fused phenyl ring; wherein each fused 5- or6-membered heteroaryl ring has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein a ring-forming carbon atom of each fused 5- or 6-memberedheteroaryl ring is optionally substituted by oxo to form a carbonylgroup; and wherein the fused 5- or 6-membered heteroaryl ring, and fusedphenyl ring are each optionally substituted with 1, 2, 3 or 4substituents independently selected from R²¹; and

each R²¹ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, halo, D, CN, OR^(a4) and NR^(c4)R^(d4); whereinsaid C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, and 5-10 membered heteroaryl are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R²²;

or two R²¹ substituents taken together with the carbon atom to whichthey are attached form a spiro 3-7-membered heterocycloalkyl ring, or aspiro C₃₋₆ cycloalkyl ring; wherein each spiro 3-7-memberedheterocycloalkyl ring has at least one ring-forming carbon atom and 1, 2or 3 ring-forming heteroatoms independently selected from N, O, and S;wherein a ring-forming carbon atom of each spiro 3-7-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the spiro 3-7membered heterocycloalkyl ringand spiro C₃₋₆ cycloalkyl ring are each optionally substituted with 1,2, 3 or 4 substituents independently selected from R²².

In some embodiments, provided herein is a compound of Formula (I),wherein:

Cy¹ is selected from phenyl and monocyclic 5-6 membered heteroarylhaving at least one ring-forming carbon atom and 1, 2, 3 or 4ring-forming nitrogen atoms; wherein the phenyl and monocyclic 5-6membered heteroaryl are each optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹⁰;

Cy^(A) is selected from 6 membered heterocycloalkyl; wherein the 6membered heterocycloalkyl has at least one ring-forming carbon atom and1 or 2 ring-forming heteroatoms independently selected from N, O, and S;wherein a ring-forming carbon atom of 6 membered heterocycloalkyl isoptionally substituted by oxo to form a carbonyl group; and wherein the6 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4substituents independently selected from R²⁰;

R¹ is selected from H, D, and C₁₋₆ alkyl;

R² is selected from H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₆₋₁₀ aryl-C₁₋₃ alkylene, halo, CN, and OR^(a7);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, and C₆₋₁₀ aryl-C₁₋₃ alkylene are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR³⁰;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, halo, D, CN, OR^(a7),C(O)NR^(c1)R^(d1) and NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₃₋₁₀cycloalkyl and 4-10 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, halo, D, CN, OR^(a3), SR^(a3), and NR^(c3)R^(d3);wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹²;

each R¹² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a5),SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5) andNR^(c5)C(O)R^(b5); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-7 memberedheterocycloalkyl, are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R²¹ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, halo, D, CN, OR^(a2),C(O)NR^(c2)R^(d2) and NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₃₋₁₀cycloalkyl and 4-10 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR²¹;

or two adjacent R²¹ substituents on the Cy^(A) ring, taken together withthe atoms to which they are attached, form a fused 5- or 6-memberedheteroaryl ring; wherein each fused 5- or 6-membered heteroaryl ring hasat least one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms independently selected from N, O, and S; wherein aring-forming carbon atom of each fused 5- or 6-membered heteroaryl ringis optionally substituted by oxo to form a carbonyl group; and whereinthe fused 5- or 6-membered heteroaryl ring, is optionally substitutedwith 1, 2, 3 or 4 substituents independently selected from R²¹; and

each R²¹ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²².

In some embodiments, provided herein is a compound of Formula (I),wherein:

Cy¹ is selected from pyrazolyl, triazolyl and phenyl; wherein thepyrazolyl, triazolyl and phenyl are each optionally substituted with 1,2, 3 or 4 substituents independently selected from R¹⁰;

Cy^(A) is 4-12 membered heterocycloalkyl; wherein each 4-12 memberedheterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3,or 4 ring-forming heteroatoms independently selected from N, O, and S;wherein the N and S are optionally oxidized; wherein a ring-formingcarbon atom of 4-12 membered heterocycloalkyl is optionally substitutedby oxo to form a carbonyl group; and wherein the 4-12 memberedheterocycloalkyl is optionally substituted with 1, 2, 3 or 4substituents independently selected from R²⁰;

R¹ is H;

R² is selected from H, D, C₁₋₆ alkyl, 5-10 membered heteroaryl, halo, CNand OR^(a7); wherein said C₁₋₆ alkyl is optionally substituted with 1, 2or 3 substituents independently selected from R³⁰;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, halo, D, CN, OR^(a1),C(O)NR^(c1)R^(d1) and NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₃₋₁₀cycloalkyl and 4-10 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR²¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl, halo, D, CN,OR^(a3) and NR^(c3)R^(d3); wherein said C₁₋₆ alkyl, 4-10 memberedheterocycloalkyl and 5-10 membered heteroaryl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹²;

each R²⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, halo, D, CN, OR^(a2),C(O)NR^(c2)R^(d2) and NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₃₋₁₀cycloalkyl and 4-10 membered heterocycloalkyl, are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR²¹;

each R²¹ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, halo, D, CN, OR^(a4) and NR^(c4)R^(d4); whereinsaid C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, are each optionally substituted with 1,2, 3, or 4 substituents independently selected from R²²;

each R³⁰ is independently selected from C₁₋₆ alkyl and phenyl;

each R^(a2), R^(c2) and R^(d2), is independently selected from H andC₁₋₆ alkyl; and

each R^(a7) is independently selected from H and C₁₋₆ alkyl.

In some embodiments, provided herein is a compound of Formula (I),wherein:

Cy¹ is selected from pyrazolyl, triazolyl, phenyl and thienopyridinyl;wherein the pyrazolyl; triazolyl and phenyl are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR¹⁰;

Cy^(A) is 4-12 membered heterocycloalkyl; wherein each 4-12 memberedheterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3,or 4 ring-forming heteroatoms independently selected from N, O, and S;wherein the N and S are optionally oxidized; wherein a ring-formingcarbon atom of 4-12 membered heterocycloalkyl is optionally substitutedby oxo to form a carbonyl group; and wherein the 4-12 memberedheterocycloalkyl is optionally substituted with 1, 2, 3 or 4substituents independently selected from R²⁰;

R¹ is H;

R² is selected from H, C₁₋₆ alkyl, 5-10 membered heteroaryl, halo, CNand OMe; wherein said C₁₋₆ alkyl is optionally substituted with 1, 2 or3 substituents independently selected from R³⁰;

each R¹⁰ is independently selected from C₁₋₆ alkyl, and 4-10 memberedheterocycloalkyl, halo; wherein said C₁₋₆ alkyl and 4-10 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R¹¹ is independently selected from 4-10 membered heterocycloalkyland 5-10 membered heteroaryl; wherein said 4-10 memberedheterocycloalkyl and 5-10 membered heteroaryl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹²;

each R²⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, and OH; wherein saidC₁₋₆ alkyl, C₃₋₁₀ cycloalkyl and 4-10 membered heterocycloalkyl, areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²¹;

each R²¹ is independently selected from C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl,and 5-10 membered heteroaryl; and

each R³⁰ is phenyl.

In some embodiments, the compound of Formula I is selected from:

1-(3-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperidin-3-ol;

3-(1-Methyl-1H-pyrazol-4-yl)-5-(1-(trifluoromethyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)-1H-pyrazolo[4,3-b]pyridine;

5-(6,7-Dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-1]pyridine;

3-Methyl-8-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-3,8-diazabicyclo[3.2.1]octan-2-one;

3-Isopropyl-1-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-1]pyridin-5-yl)piperazin-2-one;

3-Ethyl-1-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-1]pyridin-5-yl)piperazin-2-one;

3,3-Diethyl-1-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-1]pyridin-5-yl)piperazin-2-one;

3-Benzyl-1-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-1]pyridin-5-yl)piperazin-2-one;

3-(Cyclopropylmethyl)-1-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one;

1-Methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-1]pyridin-5-yl)-3-(tetrahydro-2H-pyran-4-yl)piperazin-2-one;

1-Methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-1]pyridin-5-yl)-3-(pyridin-4-ylmethyl)piperazin-2-one;

1-Methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-(1-phenylethyl)piperazin-2-one;

3-Cyclopropyl-1-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-1]pyridin-5-yl)piperazin-2-one;

1-Cyclopropyl-3-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-1]pyridin-5-yl)piperazin-2-one;

1,3,6-Trimethyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-1]pyridin-5-yl)piperazin-2-one;

3-Isopropyl-1-methyl-4-(3-(1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one;

3-Isopropyl-1-methyl-4-(3-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one;

4-(3-(3-Fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-isopropyl-1-methylpiperazin-2-one;

3-Isopropyl-1-methyl-4-(3-(thieno[3,2-c]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one;

3-Isopropyl-1-methyl-4-(3-(1-methyl-1H-1,2,3-triazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one;

4-(6-Chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1,3-dimethylpiperazin-2-one;

1,3-Dimethyl-4-(6-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one;

5-(2,4-Dimethyl-3-oxopiperazin-1-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile;

4-(6-Methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1,3-dimethylpiperazin-2-one;

4-(6-(Furan-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1,3-dimethylpiperazin-2-one;and

4-(6-Benzyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1,3-dimethylpiperazin-2-one;

or a pharmaceutically acceptable salt thereof.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

At various places in the present specification, substituents ofcompounds of the invention are disclosed in groups or in ranges. It isspecifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges. Forexample, the term “C₁₋₆ alkyl” is specifically intended to individuallydisclose methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆ alkyl.

At various places in the present specification various aryl, heteroaryl,cycloalkyl, and heterocycloalkyl rings are described. Unless otherwisespecified, these rings can be attached to the rest of the molecule atany ring member as permitted by valency. For example, the term “apyridine ring” or “pyridinyl” may refer to a pyridin-2-yl, pyridin-3-yl,or pyridin-4-yl ring.

The term “n-membered” where n is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

For compounds of the invention in which a variable appears more thanonce, each variable can be a different moiety independently selectedfrom the group defining the variable. For example, where a structure isdescribed having two R groups that are simultaneously present on thesame compound, the two R groups can represent different moietiesindependently selected from the group defined for R.

Definitions

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted.

As used herein, the term “substituted” means that a hydrogen atom isreplaced by a non-hydrogen group. It is to be understood thatsubstitution at a given atom is limited by valency.

As used herein, the term “C_(i-j),” where i and j are integers, employedin combination with a chemical group, designates a range of the numberof carbon atoms in the chemical group with i-j defining the range. Forexample, C₁₋₆ alkyl refers to an alkyl group having 1, 2, 3, 4, 5, or 6carbon atoms.

As used herein, the term “alkyl,” employed alone or in combination withother terms, refers to a saturated hydrocarbon group that may bestraight-chain or branched. In some embodiments, the alkyl groupcontains 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylmoieties include, but are not limited to, chemical groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tent-butyl, n-pentyl, 2-methyl-1-butyl, 3-pentyl, n-hexyl,1,2,2-trimethylpropyl, and the like. In some embodiments, the alkylgroup is methyl, ethyl, or propyl.

As used herein, the term “C_(i-j) alkylene,” employed alone or incombination with other terms, means a saturated divalent linkinghydrocarbon group that may be straight-chain or branched, having i to jcarbons. In some embodiments, the alkylene group contains from 1 to 4carbon atoms, from 1 to 3 carbon atoms, or from 1 to 2 carbon atoms.Examples of alkylene moieties include, but are not limited to, chemicalgroups such as methylene, ethylene, 1,1-ethylene, 1,2-ethylene ,1,3-propylene, 1,2-propylene, 1,1-propylene, isopropylene, and the like.

As used herein, “alkenyl,” employed alone or in combination with otherterms, refers to an alkyl group having one or more carbon-carbon doublebonds. In some embodiments, the alkenyl moiety contains 2 to 6 or 2 to 4carbon atoms. Example alkenyl groups include, but are not limited to,ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

As used herein, “alkynyl,” employed alone or in combination with otherterms, refers to an alkyl group having one or more carbon-carbon triplebonds. In some embodiments, the alkynyl moiety contains 2 to 6 or 2 to 4carbon atoms. Example alkynyl groups include, but are not limited to,ethynyl, propyn-1-yl, propyn-2-yl, and the like.

As used herein, “halo” or “halogen”, employed alone or in combinationwith other terms, includes fluoro, chloro, bromo, and iodo. In someembodiments, halo is F or Cl. In some embodiments, halo is F.

As used herein, the term “haloalkyl,” employed alone or in combinationwith other terms, refers to an alkyl group having up to the full valencyof halogen atom substituents, which may either be the same or different.In some embodiments, the halogen atoms are fluoro atoms. In someembodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.Example haloalkyl groups include CF₃, C₂F₅, CHF₂, CCl₃, CHCl₂, C₂Cl₅,and the like.

As used herein, the term “alkoxy,” employed alone or in combination withother terms, refers to a group of formula —O-alkyl. In some embodiments,the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examplealkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), t-butoxy, and the like. In some embodiments, alkoxy ismethoxy.

As used herein, “haloalkoxy,” employed alone or in combination withother terms, refers to a group of formula —O-(haloalkyl). In someembodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.An example haloalkoxy group is —OCF₃.

As used herein, “amino,” employed alone or in combination with otherterms, refers to NH₂.

As used herein, the term “alkylamino,” employed alone or in combinationwith other terms, refers to a group of formula —NH(alkyl). In someembodiments, the alkylamino group has 1 to 6 or 1 to 4 carbon atoms.Example alkylamino groups include methylamino, ethylamino, propylamino(e.g., n-propylamino and isopropylamino), and the like.

As used herein, the term “dialkylamino,” employed alone or incombination with other terms, refers to a group of formula —N(alkyl)₂.Example dialkylamino groups include dimethylamino, diethylamino,dipropylamino (e.g., di(n-propyl)amino and di(isopropyl)amino), and thelike. In some embodiments, each alkyl group independently has 1 to 6 or1 to 4 carbon atoms.

As used herein, the term “alkylthio,” employed alone or in combinationwith other terms, refers to a group of formula —S-alkyl. In someembodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “cycloalkyl,” employed alone or in combinationwith other terms, refers to a non-aromatic cyclic hydrocarbon includingcyclized alkyl and alkenyl groups. Cycloalkyl groups can include mono-or polycyclic (e.g., having 2, 3, or 4 fused, bridged, or spiro rings)ring systems. Also included in the definition of cycloalkyl are moietiesthat have one or more aromatic rings (e.g., aryl or heteroaryl rings)fused (i.e., having a bond in common with) to the cycloalkyl ring, forexample, benzo derivatives of cyclopentane, cyclohexene, cyclohexane,and the like, or pyrido derivatives of cyclopentane or cyclohexane.Ring-forming carbon atoms of a cycloalkyl group can be optionallysubstituted by oxo. Cycloalkyl groups also include cycloalkylidenes. Theterm “cycloalkyl” also includes bridgehead cycloalkyl groups (e.g.,non-aromatic cyclic hydrocarbon moieties containing at least onebridgehead carbon, such as admantan-1-yl) and spirocycloalkyl groups(e.g., non-aromatic hydrocarbon moieties containing at least two ringsfused at a single carbon atom, such as spiro[2.5]octane and the like).In some embodiments, the cycloalkyl group has 3 to 10 ring members, or 3to 7 ring members, or 3 to 6 ring members. In some embodiments, thecycloalkyl group is monocyclic or bicyclic. In some embodiments, thecycloalkyl group is monocyclic. In some embodiments, the cycloalkylgroup is a C₃₋₇ monocyclic cycloalkyl group. Example cycloalkyl groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl,norbornyl, norpinyl, norcarnyl, tetrahydronaphthalenyl,octahydronaphthalenyl, indanyl, and the like. In some embodiments, thecycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

As used herein, the term “heterocycloalkyl,” employed alone or incombination with other terms, refers to a non-aromatic ring or ringsystem, which may optionally contain one or more alkenylene oralkynylene groups as part of the ring structure, which has at least oneheteroatom ring member independently selected from nitrogen, sulfur,oxygen, and phosphorus. Heterocycloalkyl groups can include mono- orpolycyclic (e.g., having 2, 3 or 4 fused, bridged, or spiro rings) ringsystems. In some embodiments, the heterocycloalkyl group is a monocyclicor bicyclic group having 1, 2, 3, or 4 heteroatoms independentlyselected from nitrogen, sulfur and oxygen. Also included in thedefinition of heterocycloalkyl are moieties that have one or morearomatic rings (e.g., aryl or heteroaryl rings) fused (i.e., having abond in common with) to the non-aromatic heterocycloalkyl ring, forexample, 1,2,3,4-tetrahydro-quinoline and the like. Heterocycloalkylgroups can also include bridgehead heterocycloalkyl groups (e.g., aheterocycloalkyl moiety containing at least one bridgehead atom, such asazaadmantan-1-yl and the like) and spiroheterocycloalkyl groups (e.g., aheterocycloalkyl moiety containing at least two rings fused at a singleatom, such as [1,4-dioxa-8-aza-spiro[4.5]decan-N-yl] and the like). Insome embodiments, the heterocycloalkyl group has 3 to 10 ring-formingatoms, 4 to 10 ring-forming atoms, or 3 to 8 ring forming atoms. In someembodiments, the heterocycloalkyl group has 1 to 5 heteroatoms, 1 to 4heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms. The carbon atomsor heteroatoms in the ring(s) of the heterocycloalkyl group can beoxidized to form a carbonyl, an N-oxide, or a sulfonyl group (or otheroxidized linkage) or a nitrogen atom can be quaternized. In someembodiments, the heterocycloalkyl portion is a C₂₋₇ monocyclicheterocycloalkyl group. In some embodiments, the heterocycloalkyl groupis a morpholine ring, pyrrolidine ring, piperazine ring, piperidinering, dihydropyran ring, tetrahydropyran ring, tetrahyropyridine,azetidine ring, or tetrahydrofuran ring. In some embodiments, theheterocycloalkyl is a 4-7 membered heterocycloalkyl moiety having carbonand 1, 2, or 3 heteroatoms independently selected from N, O and S. Insome embodiments, the heterocycloalkyl is 4-10 membered heterocycloalkylmoiety having carbon and 1, 2, or 3 heteroatoms independently selectedfrom N, O and S. As used herein, the term “aryl,” employed alone or incombination with other terms, refers to a monocyclic or polycyclic(e.g., having 2 fused rings) aromatic hydrocarbon moiety, such as, butnot limited to, phenyl, 1-naphthyl, 2-naphthyl, and the like. In someembodiments, aryl groups have from 6 to 10 carbon atoms or 6 carbonatoms. In some embodiments, the aryl group is a monocyclic or bicyclicgroup. In some embodiments, the aryl group is phenyl or naphthyl.

As used herein, the term “heteroaryl,” employed alone or in combinationwith other terms, refers to a monocyclic or polycyclic (e.g., having 2or 3 fused rings) aromatic hydrocarbon moiety, having one or moreheteroatom ring members independently selected from nitrogen, sulfur andoxygen. In some embodiments, the heteroaryl group is a monocyclic orbicyclic group having 1, 2, 3, or 4 heteroatoms independently selectedfrom nitrogen, sulfur and oxygen. Example heteroaryl groups include, butare not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,triazinyl, furyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl,oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, pyrrolyl,azolyl, quinolinyl, isoquinolinyl, benzisoxazolyl,imidazo[1,2-b]thiazolyl or the like. The carbon atoms or heteroatoms inthe ring(s) of the heteroaryl group can be oxidized to form a carbonyl,an N-oxide, or a sulfonyl group (or other oxidized linkage) or anitrogen atom can be quaternized, provided the aromatic nature of thering is preserved. In one embodiment the heteroaryl group is a 5 to 10membered heteroaryl group. In another embodiment the heteroaryl group isa 5 to 6 membered heteroaryl group. In some embodiments, the heteroarylis a 5-6 membered heteroaryl moiety having carbon and 1, 2, or 3heteroatoms independently selected from N, O and S. In some embodiments,the heteroaryl is a 5-10 membered heteroaryl moiety having carbon and 1,2, or 3 heteroatoms independently selected from N, O and S.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out bymethods known in the art. An example method includes fractionalrecrystallizaion using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids. Other resolvingagents suitable for fractional crystallization methods includestereoisomerically pure forms of methylbenzylamine (e.g., S and R forms,or diastereomerically pure forms), 2-phenylglycinol, norephedrine,ephedrine, N-methylephedrine, cyclohexylethylamine,1,2-diaminocyclohexane, and the like. Resolution of racemic mixtures canalso be carried out by elution on a column packed with an opticallyactive resolving agent (e.g., dinitrobenzoylphenylglycine). Suitableelution solvent composition can be determined by one skilled in the art.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, enamine-imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system, forexample, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

Compounds of the invention also include all isotopes of atoms occurringin the intermediates or final compounds. Isotopes include those atomshaving the same atomic number but different mass numbers. For example,isotopes of hydrogen include tritium and deuterium.

The term, “compound,” as used herein is meant to include allstereoisomers, geometric iosomers, tautomers, and isotopes of thestructures depicted.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,in the form of hydrates and solvates) or can be isolated.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compounds of theinvention. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds of the invention, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present invention include the non-toxic salts ofthe parent compound formed, for example, from non-toxic inorganic ororganic acids. The pharmaceutically acceptable salts of the presentinvention can be synthesized from the parent compound which contains abasic or acidic moiety by conventional chemical methods. Generally, suchsalts can be prepared by reacting the free acid or base forms of thesecompounds with a stoichiometric amount of the appropriate base or acidin water or in an organic solvent, or in a mixture of the two;generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g.,methanol, ethanol, iso-propanol, or butanol) or acetonitrile (ACN) arepreferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), eachof which is incorporated herein by reference in its entirety.

The following abbreviations may be used herein: AcOH (acetic acid); Ac₂O(acetic anhydride); aq. (aqueous); atm. (atmosphere(s)); Boc(t-butoxycarbonyl); br (broad); Cbz (carboxybenzyl); calc. (calculated);d (doublet); dd (doublet of doublets); DCM (dichloromethane); DEAD(diethyl azodicarboxylate); DIAD (N,N′-diisopropyl azidodicarboxylate);DIPEA (N,N-diisopropylethylamine); DMF (N,N-dimethylformamide); Et(ethyl); EtOAc (ethyl acetate); g (gram(s)); h (hour(s)); HATU(N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate); HCl (hydrochloric acid); HPLC (high performanceliquid chromatography); Hz (hertz); J (coupling constant); LCMS (liquidchromatography-mass spectrometry); m (multiplet); M (molar); mCPBA(3-chloroperoxybenzoic acid); MgSO₄ (magnesium sulfate); MS (Massspectrometry); Me (methyl); MeCN (acetonitrile); MeOH (methanol); mg(milligram(s)); min. (minutes(s)); mL (milliliter(s)); mmol(millimole(s)); N (normal); NaHCO₃ (sodium bicarbonate); NaOH (sodiumhydroxide); Na₂SO₄ (sodium sulfate); NH₄Cl (ammonium chloride); NH₄OH(ammonium hydroxide); nM (nanomolar); NMR (nuclear magnetic resonancespectroscopy); OTf (trifluoromethanesulfonate); Pd (palladium); Ph(phenyl); pM (picomolar); PMB (para-methoxybenzyl), POCl₃ (phosphorylchloride); RP-HPLC (reverse phase high performance liquidchromatography); s (singlet); t (triplet or tertiary); TBS(tert-butyldimethylsilyl); tert (tertiary); tt (triplet of triplets);t-Bu (tert-butyl); TFA (trifluoroacetic acid); THF (tetrahydrofuran); μg(microgram(s)); μL (microliter(s)); μM (micromolar); wt % (weightpercent).

Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and according to variouspossible synthetic routes.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons,Inc., New York (1999), which is incorporated herein by reference in itsentirety.

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), ormass spectrometry, or by chromatography such as high performance liquidchromatography (HPLC) or thin layer chromatography.

The expressions, “ambient temperature,” “room temperature,” and “r.t.”,as used herein, are understood in the art, and refer generally to atemperature, e.g. a reaction temperature, that is about the temperatureof the room in which the reaction is carried out, for example, atemperature from about 20° C. to about 30° C.

Compounds described herein can be prepared by one skilled in the artaccording to preparatory routes known in the literature. Examplesynthetic methods for preparing compounds of the invention are providedin the Schemes below.

Compounds of formula 1-4 can be prepared via the synthetic routeoutlined in Scheme 1. A halogenation reaction of 1-1 can be carried outusing an appropriate reagent, such as N-iodosuccinimide, followed by NHprotection to afford compounds of formula 1-2. The compounds of formula1-2 can be cross-coupled with Cy¹-M, in which M is a boronic acid,boronic ester or an appropriately substituted metal [e.g., M is B(OR)₂,Sn(Alkyl)₃, or Zn—Hal], under standard Suzuki Cross-Coupling conditions(e.g., in the presence of a palladium catalyst and a suitable base), orstandard Stille cross-coupling conditions (e.g., in the presence of apalladium catalyst) (ACS Catalysis 2015, 5, 3040-3053), or standardNegishi cross-coupling conditions (e.g., in the presence of a palladiumcatalyst) (ACS Catalysis 2016, 6, 1540-1552) to generate compounds offormula 1-3. Buchwald-Hartwig reaction of 1-3 with an appropriate aminecan then be carried out using standard Buchwald-Hartwig cross-couplingconditions (e.g., in the presence of a palladium catalyst and a suitablebase) (Chem. Sci. 2011, 2, 27-50), followed by deprotection of theprotective group to afford compounds of formula 1-4.

Compounds of formula 2-2 and 2-3 can be prepared via the synthetic routeoutlined in Scheme 2. A Buchwald-Hartwig reaction of 1-3 (prepared usingprocedures from Scheme 1) with an appropriate amine can be carried outusing standard Buchwald-Hartwig cross-coupling conditions (e.g., in thepresence of a palladium catalyst and a suitable base) to affordcompounds of formula 2-1. Alkylation of 2-1 can be conducted usingappropriate base (e.g. LDA) and R²⁰-Hal (Hal is a halide, such as Cl,Br, or I) to afford mono and double alkylated products 2-2 and 2-3.

Compounds of formula 1-4 can be alternatively prepared via the syntheticroute outlined in Scheme 3. Protection of 1-1 results in the formationof compounds of formula 3-1. Reaction of 3-1 with an appropriate amineunder standard Buchwald-Hartwig cross-coupling conditions (e.g., in thepresence of a palladium catalyst and a suitable base) followed bydeprotection can afford compounds of formula 3-2. A halogenationreaction of 3-2 can be carried out using an appropriate reagent, such asN-iodosuccinimide, followed by NH protection results in compounds offormula 3-3. The compounds 3-3 can then be cross-coupled with Cy^(l)-M,where M is a boronic acid, boronic ester or an appropriately substitutedmetal [e.g., M is B(OR)₂, Sn(Alkyl)₃, or Zn-Hal], under standard Suzukicross-coupling conditions (e.g., in the presence of a palladium catalystand a suitable base) (Tetrahedron 2002, 58, 9633-9695), or standardStille cross-coupling conditions (e.g., in the presence of a palladiumcatalyst), or standard Negishi cross-coupling conditions (e.g., in thepresence of a palladium catalyst) to generate intermediate 3-4, whichcan then be deprotected to afford compounds of formula 1-4.

Compounds of formula 4-8 can be prepared via the synthetic routeoutlined in Scheme 4. A halogenation reaction of 4-1 can be carried outusing an appropriate reagent, such as N-bromosuccinimide, followed byprotection with acetic anhydride to afford compounds of formula 4-2. Areaction of 4-2 with isopentyl nitrite results in the formation of 4-3,which can then be deprotected to afford 4-4. Halogenation and protectionof 4-4 using N-iodosuccinimide and an appropriate protective group candeliver compound 4-5. A cross-coupling reaction can be performed between4-5 and Cy¹-M in which M is a boronic acid, boronic ester or anappropriately substituted metal [e.g., M is B(OR)₂, Sn(Alkyl)₃, orZn-Hal], under standard Suzuki cross-coupling conditions (e.g., in thepresence of a palladium catalyst and a suitable base), or standardStille cross-coupling conditions (e.g., in the presence of a palladiumcatalyst), or standard Negishi cross-coupling conditions (e.g., in thepresence of a palladium catalyst) to generate compounds of formula 4-6,which can be used in Buchwald-Hartwig cross-coupling reaction to providecompounds of formula 4-7. Finally, another cross-coupling reactionbetween 4-7 and an appropriate coupling partner can be performed usingsimilar conditions as described for the transformation from 4-5 to 4-6or transformation from 4-6 to 4-7 to afford compounds of formula 4-8.

Methods of Use

Compounds of the present disclosure can inhibit the activity of the FGFRenzyme. For example, compounds of the present disclosure can be used toinhibit activity of an FGFR enzyme in a cell or in an individual orpatient in need of inhibition of the enzyme by administering aninhibiting amount of one or more compounds of the present disclosure tothe cell, individual, or patient. Compounds of the present disclosurecan be used to inhibit activity of the FGFR3 enzyme in a cell or in anindividual or patient in need of inhibition of the enzyme byadministering an inhibiting amount of one or more compounds of thepresent disclosure to the cell, individual, or patient.

As FGFR inhibitors, the compounds of the present disclosure are usefulin the treatment of various diseases associated with abnormal expressionor activity of the FGFR enzyme or FGFR ligands. Compounds which inhibitFGFR will be useful in providing a means of preventing the growth orinducing apoptosis in tumors, particularly by inhibiting angiogenesis.It is therefore anticipated that compounds of the present disclosurewill prove useful in treating or preventing proliferative disorders suchas cancers. In particular, tumors with activating mutants of receptortyrosine kinases or upregulation of receptor tyrosine kinases may beparticularly sensitive to the inhibitors.

In certain embodiments, the disclosure provides a method for treating aFGFR-mediated disorder in a patient in need thereof, comprising the stepof administering to said patient a compound according to the invention,or a pharmaceutically acceptable composition thereof.

In some embodiments, diseases and indications that are treatable usingthe compounds of the present disclosure include, but are not limited tohematological cancers, sarcomas, lung cancers, gastrointestinal cancers,genitourinary tract cancers, liver cancers, bone cancers, nervous systemcancers, gynecological cancers, and skin cancers.

Exemplary hematological cancers include lymphomas and leukemias such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsedor refractory NHL and recurrent follicular), Hodgkin lymphoma,myeloproliferative diseases (e.g., primary myelofibrosis (PMF),polycythemia vera (PV), essential thrombocytosis (ET), 8p11myeloproliferative syndrome), myelodysplasia syndrome (MDS), T-cellacute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-celllymphoma, adult T-cell leukemia, Waldenstrom's Macroglubulinemia, hairycell lymphoma, marginal zone lymphoma, chronic myelogenic lymphoma andBurkitt's lymphoma.

Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma,myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma,lymphosarcoma, leiomyosarcoma, and teratoma.

Exemplary lung cancers include non-small cell lung cancer (NSCLC), smallcell lung cancer, bronchogenic carcinoma (squamous cell,undifferentiated small cell, undifferentiated large cell,adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma,chondromatous hamartoma, mesothelioma, pavicellular and non-pavicellularcarcinoma, bronchial adenoma and pleuropulmonary blastoma.

Exemplary gastrointestinal cancers include cancers of the esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (exocrinepancreatic carcinoma, ductal adenocarcinoma, insulinoma, glucagonoma,gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma,lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma,lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubularadenoma, villous adenoma, hamartoma, leiomyoma), colorectal cancer, gallbladder cancer and anal cancer.

Exemplary genitourinary tract cancers include cancers of the kidney(adenocarcinoma, Wilm's tumor [nephroblastoma], renal cell carcinoma),bladder and urethra (squamous cell carcinoma, transitional cellcarcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis(seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, lipoma) and urothelial carcinoma.

Exemplary liver cancers include hepatoma (hepatocellular carcinoma),cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellularadenoma, and hemangioma.

Exemplary bone cancers include, for example, osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant celltumors

Exemplary nervous system cancers include cancers of the skull (osteoma,hemangioma, granuloma, xanthoma, osteitis deformans), meninges(meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma,meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma,glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma,congenital tumors, neuro-ectodermal tumors), and spinal cord(neurofibroma, meningioma, glioma, sarcoma), neuroblastoma,Lhermitte-Duclos disease and pineal tumors.

Exemplary gynecological cancers include cancers of the breast (ductalcarcinoma, lobular carcinoma, breast sarcoma, triple-negative breastcancer, HER2-positive breast cancer, inflammatory breast cancer,papillary carcinoma), uterus (endometrial carcinoma), cervix (cervicalcarcinoma, pre -tumor cervical dysplasia), ovaries (ovarian carcinoma(serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma), and fallopian tubes (carcinoma).

Exemplary skin cancers include melanoma, basal cell carcinoma, squamouscell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, molesdysplastic nevi, lipoma, angioma, dermatofibroma, and keloids.

Exemplary head and neck cancers include glioblastoma, melanoma,rhabdosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinomas,adenocarcinomas, oral cancer, laryngeal cancer, nasopharyngeal cancer,nasal and paranasal cancers, thyroid and parathyroid cancers, tumors ofthe eye, tumors of the lips and mouth and squamous head and neck cancer.

The compounds of the present disclosure can also be useful in theinhibition of tumor metastases.

In addition to oncogenic neoplasms, the compounds of the invention areuseful in the treatment of skeletal and chondrocyte disorders including,but not limited to, achrondroplasia, hypochondroplasia, dwarfism,thanatophoric dysplasia (TD) (clinical forms TD I and TD II), Apertsyndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevensoncutis gyrate syndrome, Pfeiffer syndrome, and craniosynostosissyndromes. In some embodiments, the present disclosure provides a methodfor treating a patient suffering from a skeletal and chondrocytedisorder.

In some embodiments, compounds described herein can be used to treatAlzheimer's disease, HIV, or tuberculosis.

As used herein, the term “8p11 myeloproliferative syndrome” is meant torefer to myeloid/lymphoid neoplasms associated with eosinophilia andabnormalities of FGFR1.

As used herein, the term “cell” is meant to refer to a cell that is invitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can bepart of a tissue sample excised from an organism such as a mammal. Insome embodiments, an in vitro cell can be a cell in a cell culture. Insome embodiments, an in vivo cell is a cell living in an organism suchas a mammal.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” the FGFR enzyme with a compound described hereinincludes the administration of a compound described herein to anindividual or patient, such as a human, having FGFR, as well as, forexample, introducing a compound described herein into a samplecontaining a cellular or purified preparation containing the FGFRenzyme.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent such as an amountof any of the solid forms or salts thereof as disclosed herein thatelicits the biological or medicinal response in a tissue, system,animal, individual or human that is being sought by a researcher,veterinarian, medical doctor or other clinician. An appropriate“effective” amount in any individual case may be determined usingtechniques known to a person skilled in the art.

The phrase “pharmaceutically acceptable” is used herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, immunogenicity or other problem orcomplication, commensurate with a reasonable benefit/risk ratio.

As used herein, the phrase “pharmaceutically acceptable carrier orexcipient” refers to a pharmaceutically-acceptable material,composition, or vehicle, such as a liquid or solid filler, diluent,solvent, or encapsulating material. Excipients or carriers are generallysafe, non-toxic and neither biologically nor otherwise undesirable andinclude excipients or carriers that are acceptable for veterinary use aswell as human pharmaceutical use. In one embodiment, each component is“pharmaceutically acceptable” as defined herein. See, e.g., Remington:The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams &Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients,6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the AmericanPharmaceutical Association: 2009; Handbook of Pharmaceutical Additives,3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007;Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRCPress LLC: Boca Raton, Fla., 2009.

As used herein, the term “treating” or “treatment” refers to inhibitingthe disease; for example, inhibiting a disease, condition or disorder inan individual who is experiencing or displaying the pathology orsymptomatology of the disease, condition or disorder (i.e., arrestingfurther development of the pathology and/or symptomatology) orameliorating the disease; for example, ameliorating a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,reversing the pathology and/or symptomatology) such as decreasing theseverity of disease.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, can also beprovided in combination in a single embodiment (while the embodimentsare intended to be combined as if written in multiply dependent form).Conversely, various features of the invention which are, for brevity,described in the context of a single embodiment, can also be providedseparately or in any suitable subcombination.

Combination Therapy

One or more additional pharmaceutical agents or treatment methods suchas, for example, anti-viral agents, chemotherapeutics or otheranti-cancer agents, immune enhancers, immunosuppressants, radiation,anti-tumor and anti-viral vaccines, cytokine therapy (e.g., IL2, GM-CSF,etc.), and/or tyrosine kinase inhibitors can be used in combination withcompounds described herein for treatment of FGFR-associated diseases,disorders or conditions, or diseases or conditions as described herein.The agents can be combined with the present compounds in a single dosageform, or the agents can be administered simultaneously or sequentiallyas separate dosage forms.

Compounds described herein can be used in combination with one or moreother kinase inhibitors for the treatment of diseases, such as cancer,that are impacted by multiple signaling pathways. For example, acombination can include one or more inhibitors of the following kinasesfor the treatment of cancer: Akt1, Akt2, Akt3, TGF-βR, Pim, PKA, PKG,PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR,HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR, CSFIR, KIT,FLK-II, KDR/FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron,Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/F1t2, Flt4, EphA1, EphA2, EphA3,EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL,ALK and B-Raf. Additionally, the solid forms of the FGFR inhibitor asdescribed herein can be combined with inhibitors of kinases associatedwith the PIK3/Akt/mTOR signaling pathway, such as PI3K, Akt (includingAkt1, Akt2 and Akt3) and mTOR kinases.

In some embodiments, compounds described herein can be used incombination with one or more inhibitors of the enzyme or proteinreceptors such as HPK1, SBLB, TUT4, A2A/A2B, CD47, CDK2, STING, ALK2,LIN28, ADAR1, MAT2a, RIOK1, HDAC8, WDR5, SMARCA2, and DCLK1 for thetreatment of diseases and disorders. Exemplary diseases and disordersinclude cancer, infection, inflammation and neurodegenerative disorders.

In some embodiments, compouds described herein can be used incombination with a therapeutic agent that targets an epigeneticregulator. Examples of epigenetic regulators include bromodomaininhibitors, the histone lysine methyltransferases, histone argininemethyl transferases, histone demethylases, histone deacetylases, histoneacetylases, and DNA methyltransferases. Histone deacetylase inhibitorsinclude, e.g., vorinostat.

For treating cancer and other proliferative diseases, compoundsdescribed herein can be used in combination with targeted therapies,including JAK kinase inhibitors (Ruxolitinib, additional JAK1/2 andJAK1-selective, baricitinib or INCB39110), Pim kinase inhibitors (e.g.,LGH447, INCB053914 and SGI-1776), PI3 kinase inhibitors includingPI3K-delta selective and broad spectrum PI3K inhibitors (e.g., INCB50465and INCB54707), PI3K-gamma inhibitors such as PI3K-gamma selectiveinhibitors, MEK inhibitors, CSF1R inhibitors (e.g., PLX3397 andLY3022855), TAM receptor tyrosine kinases inhibitors (Tyro-3, Axl, andMer; e.g., INCB81776), angiogenesis inhibitors, interleukin receptorinhibitors, Cyclin Dependent kinase inhibitors, BRAF inhibitors, mTORinhibitors, proteasome inhibitors (Bortezomib, Carfilzomib),HDAC-inhibitors (panobinostat, vorinostat), DNA methyl transferaseinhibitors, dexamethasone, bromo and extra terminal family membersinhibitors (for example, bromodomain inhibitors or BET inhibitors, suchas OTX015, CPI-0610, INCB54329 or INCB57643), LSD1 inhibitors (e.g.,GSK2979552, INCB59872 and INCB60003), arginase inhibitors (e.g.,INCB1158), indoleamine 2,3-dioxygenase inhibitors (e.g., epacadostat,NLG919 or BMS-986205), PARP inhibiors (e.g., olaparib or rucaparib),inhibitors of BTK such as ibrutinib, c-MET inhibitors (e.g.,capmatinib), an ALK2 inhibitor (e.g., INCB00928); or combinationsthereof.

For treating cancer and other proliferative diseases, compoundsdescribed herein can be used in combination with chemotherapeuticagents, agonists or antagonists of nuclear receptors, or otheranti-proliferative agents. Compounds described herein can also be usedin combination with a medical therapy such as surgery or radiotherapy,e.g., gamma-radiation, neutron beam radiotherapy, electron beamradiotherapy, proton therapy, brachytherapy, and systemic radioactiveisotopes.

Examples of suitable chemotherapeutic agents include any of: abarelix,abiraterone, afatinib, aflibercept, aldesleukin, alemtuzumab,alitretinoin, allopurinol, altretamine, amidox, amsacrine, anastrozole,aphidicolon, arsenic trioxide, asparaginase, axitinib, azacitidine,bevacizumab, bexarotene, baricitinib, bendamustine, bicalutamide,bleomycin, bortezombi, bortezomib, brivanib, buparlisib, busulfanintravenous, busulfan oral, calusterone, camptosar, capecitabine,carboplatin, carmustine, cediranib, cetuximab, chlorambucil, cisplatin,cladribine, clofarabine, crizotinib, cyclophosphamide, cytarabine,dacarbazine, dacomitinib, dactinomycin, dalteparin sodium, dasatinib,dactinomycin, daunorubicin, decitabine, degarelix, denileukin,denileukin diftitox, deoxycoformycin, dexrazoxane, didox, docetaxel,doxorubicin, droloxafine, dromostanolone propionate, eculizumab,enzalutamide, epidophyllotoxin, epirubicin, epothilones, erlotinib,estramustine, etoposide phosphate, etoposide, exemestane, fentanylcitrate, filgrastim, floxuridine, fludarabine, fluorouracil, flutamide,fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelinacetate, histrelin acetate, ibritumomab tiuxetan, idarubicin,idelalisib, ifosfamide, imatinib mesylate, interferon alfa 2a,irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin,leuprolide acetate, levamisole, lonafarnib, lomustine, meclorethamine,megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen,mithramycin, mitomycin C, mitotane, mitoxantrone, nandrolonephenpropionate, navelbene, necitumumab, nelarabine, neratinib,nilotinib, nilutamide, niraparib, nofetumomab, oserelin, oxaliplatin,paclitaxel, pamidronate, panitumumab, panobinostat, pazopanib,pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin,pilaralisib, pipobroman, plicamycin, ponatinib, porfimer, prednisone,procarbazine, quinacrine, ranibizumab, rasburicase, regorafenib,reloxafine, revlimid, rituximab, rucaparib, ruxolitinib, sorafenib,streptozocin, sunitinib, sunitinib maleate, tamoxifen, tegafur,temozolomide, teniposide, testolactone, tezacitabine, thalidomide,thioguanine, thiotepa, tipifarnib, topotecan, toremifene, tositumomab,trastuzumab, tretinoin, triapine, trimidox, triptorelin, uracil mustard,valrubicin, vandetanib, vinblastine, vincristine, vindesine,vinorelbine, vorinostat, veliparib, talazoparib, and zoledronate.

Cancer cell growth and survival can be impacted by dysfunction inmultiple signaling pathways. Thus, it is useful to combine differentenzyme/protein/receptor inhibitors, exhibiting different preferences inthe targets which they modulate the activities of, to treat suchconditions. Targeting more than one signaling pathway (or more than onebiological molecule involved in a given signaling pathway) may reducethe likelihood of drug-resistance arising in a cell population, and/orreduce the toxicity of treatment.

One or more additional pharmaceutical agents such as, for example,chemotherapeutics, anti-inflammatory agents, steroids,immunosuppressants, immune-oncology agents, metabolic enzyme inhibitors,chemokine receptor inhibitors, and phosphatase inhibitors, as well astargeted therapies such as Bcr-Abl, Flt-3, EGFR, HER2, JAK, c-MET,VEGFR, PDGFR, c-Kit, IGF-1R, RAF, FAK, CDK2, and CDK4/6 kinaseinhibitors such as, for example, those described in WO 2006/056399 canbe used in combination with the treatment methods and regimens of thepresent disclosure for treatment of cancers and solid tumors. Otheragents such as therapeutic antibodies can be used in combination withthe treatment methods and regimens of the present disclosure fortreatment of cancers and solid tumors. The one or more additionalpharmaceutical agents can be administered to a patient simultaneously orsequentially.

The treatment methods as disclosed herein can be used in combinationwith one or more other enzyme/protein/receptor inhibitors therapies forthe treatment of diseases, such as cancer and other diseases ordisorders described herein. For example, the treatment methods andregimens of the present disclosure can be combined with one or moreinhibitors of the following kinases for the treatment of cancer: Akt1,Akt2, Akt3, BCL2, CDK2, CDK4/6, TGF-βR, PKA, PKG, PKC, CaM-kinase,phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4,INS-R, IDH2, IGF-1R, IR-R, PDGFαR, PDGFβR, PI3K (alpha, beta, gamma,delta, and multiple or selective), CSF1R, KIT, FLK-II, KDR/FLK-1, FLK-4,flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, PARP, Ron, Sea, TRKA, TRKB,TRKC, TAM kinases (Axl, Mer, Tyro3), FLT3, VEGFR/Flt2, Flt4, EphA1,EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK,FRK, JAK, ABL, ALK and B-Raf. Non-limiting examples of inhibitors thatcan be combined with the treatment methods and regimens of the presentdisclosure for treatment of cancer include an FGFR inhibitor (FGFR1,FGFR2, FGFR3 or FGFR4, e.g., pemigatinib (INCB54828), INCB62079), anEGFR inhibitor (also known as ErB-1 or HER-1; e.g. erlotinib, gefitinib,vandetanib, orsimertinib, cetuximab, necitumumab, or panitumumab), aVEGFR inhibitor or pathway blocker (e.g. bevacizumab, pazopanib,sunitinib, sorafenib, axitinib, regorafenib, ponatinib, cabozantinib,vandetanib, ramucirumab, lenvatinib, ziv-aflibercept), a PARP inhibitor(e.g. olaparib, rucaparib, veliparib or niraparib), a JAK inhibitor(JAK1 and/or JAK2, e.g., ruxolitinib, baricitinib, itacitinib(INCB39110), an LSD1 inhibitor (e.g., INCB59872 and INCB60003), a TDOinhibitor, a PI3K-delta inhibitor (e.g., INCB50465 and INCB50797), aPI3K-gamma inhibitor such as PI3K-gamma selective inhibitor, a Piminhibitor (e.g., INCB53914), a CSF1R inhibitor, a TAM receptor tyrosinekinases (Tyro-3, Axl, and Mer), an adenosine receptor antagonist (e.g.,A2a/A2b receptor antagonist), an HPK1 inhibitor, a chemokine receptorinhibitor (e.g. CCR2 or CCRS inhibitor), a SHP1/2 phosphatase inhibitor,a histone deacetylase inhibitor (HDAC) such as an HDAC8 inhibitor, anangiogenesis inhibitor, an interleukin receptor inhibitor, bromo andextra terminal family members inhibitors (for example, bromodomaininhibitors or BET inhibitors such as INCB54329 and INCB57643), c-METinhibitors (e.g., capmatinib), an anti-CD19 antibody (e.g.,tafasitamab), an ALK2 inhibitor (e.g., INCB00928); or combinationsthereof.

In some embodiments, the treatment methods described herein are combinedwith administration of a PI3K6 inhibitor. In some embodiments, thetreatment methods described herein are combined with administration of aJAK inhibitor. In some embodiments, the treatment methods describedherein are combined with administration of a JAK1 or JAK2 inhibitor(e.g., baricitinib or ruxolitinib). In some embodiments, the treatmentmethods described herein are combined with administration of a JAK1inhibitor. In some embodiments, the treatment methods described hereinare combined with administration of a JAK1 inhibitor, which is selectiveover JAK2.

Example antibodies that can be administered in combination therapyinclude, but are not limited to, trastuzumab (e.g., anti-HER2),ranibizumab (e.g., anti-VEGF-A), bevacizumab (AVASTIN™, e.g.,anti-VEGF), panitumumab (e.g., anti-EGFR), cetuximab (e.g., anti-EGFR),rituxan (e.g., anti-CD20), and antibodies directed to c-MET.

One or more of the following agents may be administered to a patient incombination with the treatment methods of the present disclosure and arepresented as a non-limiting list: a cytostatic agent, cisplatin,doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar,topotecan, paclitaxel, docetaxel, epothilones, tamoxifen,5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH66336, R115777, L778,123, BMS 214662, IRESSA™ (gefitinib), TARCEVA™(erlotinib), antibodies to EGFR, intron, ara-C, adriamycin, cytoxan,gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan,chlorambucil, pipobroman, triethylenemelamine,triethylenethiophosphoramine, busulfan, carmustine, lomustine,streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine,6-thioguanine, fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN™(oxaliplatin), pentostatine, vinblastine, vincristine, vindesine,bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin,idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase,teniposide 17.alpha.-ethinylestradiol, diethylstilbestrol, testosterone,Prednisone, Fluoxymesterone, Dromostanolone propionate, testolactone,megestrolacetate, methylprednisolone, methyltestosterone, prednisolone,triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide,estramustine, medroxyprogesteroneacetate, leuprolide, flutamide,toremifene, goserelin, carboplatin, hydroxyurea, amsacrine,procarbazine, mitotane, mitoxantrone, levamisole, navelbene,anastrazole, letrazole, capecitabine, reloxafine, droloxafine,hexamethylmelamine, avastin, HERCEPTIN™ (trastuzumab), BEXXAR™(tositumomab), VELCADE™ (bortezomib), ZEVALIN™ (ibritumomab tiuxetan),TRISENOX™ (arsenic trioxide), XELODA™ (capecitabine), vinorelbine,porfimer, ERBITUX™ (cetuximab), thiotepa, altretamine, melphalan,trastuzumab, lerozole, fulvestrant, exemestane, ifosfomide, rituximab,C225 (cetuximab), Campath (alemtuzumab), clofarabine, cladribine,aphidicolon, rituxan, sunitinib, dasatinib, tezacitabine, Sml1,fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, andMDL-101,731.

The treatment methods and regimens of the present disclosure can furtherbe used in combination with other methods of treating cancers, forexample by chemotherapy, irradiation therapy, tumor-targeted therapy,adjuvant therapy, immunotherapy or surgery. Examples of immunotherapyinclude cytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2),CRS-207 immunotherapy, cancer vaccine, monoclonal antibody, bispecificor multi-specific antibody, antibody drug conjugate, adoptive T celltransfer, Toll receptor agonists, RIG-I agonists, oncolytic virotherapyand immunomodulating small molecules, including thalidomide or JAK1/2inhibitor, PI3K6 inhibitor and the like. The compounds can beadministered in combination with one or more anti-cancer drugs, such asa chemotherapeutic agent. Examples of chemotherapeutics include any of:abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol,altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine,bevacizumab, bexarotene, baricitinib, bleomycin, bortezomib, busulfanintravenous, busulfan oral, calusterone, capecitabine, carboplatin,carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine,cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparinsodium, dasatinib, daunorubicin, decitabine, denileukin, denileukindiftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolonepropionate, eculizumab, epacadostat, epirubicin, erlotinib,estramustine, etoposide phosphate, etoposide, exemestane, fentanylcitrate, filgrastim, floxuridine, fludarabine, fluorouracil,fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelinacetate, histrelin acetate, ibritumomab tiuxetan, idarubicin,ifosfamide, imatinib mesylate, interferon alfa 2a, irinotecan, lapatinibditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate,levamisole, lomustine, meclorethamine, megestrol acetate, melphalan,mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane,mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab,oxaliplatin, paclitaxel, pamidronate, panitumumab, pegaspargase,pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin,procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib,sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen,temozolomide, teniposide, testolactone, thalidomide, thioguanine,thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin,uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine,vorinostat, and zoledronate.

Additional examples of chemotherapeutics include proteosome inhibitors(e.g., bortezomib), thalidomide, revlimid, and DNA-damaging agents suchas melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide,carmustine, and the like.

Example steroids include corticosteroids such as dexamethasone orprednisone.

Example Bcr-Abl inhibitors include imatinib mesylate (GLEEVAC™),nilotinib, dasatinib, bosutinib, and ponatinib, and pharmaceuticallyacceptable salts. Other example suitable Bcr-Abl inhibitors include thecompounds, and pharmaceutically acceptable salts thereof, of the generaand species disclosed in U.S. Pat. No. 5,521,184, WO 04/005281, and U.S.Ser. No. 60/578,491.

Example suitable Flt-3 inhibitors include midostaurin, lestaurtinib,linifanib, sunitinib, sunitinib, maleate, sorafenib, quizartinib,crenolanib, pacritinib, tandutinib, PLX3397 and ASP2215, and theirpharmaceutically acceptable salts. Other example suitable Flt-3inhibitors include compounds, and their pharmaceutically acceptablesalts, as disclosed in WO 03/037347, WO 03/099771, and WO 04/046120.

Example suitable RAF inhibitors include dabrafenib, sorafenib, andvemurafenib, and their pharmaceutically acceptable salts. Other examplesuitable RAF inhibitors include compounds, and their pharmaceuticallyacceptable salts, as disclosed in WO 00/09495 and WO 05/028444.

Example suitable FAK inhibitors include VS-4718, VS-5095, VS-6062,VS-6063, BI853520, and GSK2256098, and their pharmaceutically acceptablesalts. Other example suitable FAK inhibitors include compounds, andtheir pharmaceutically acceptable salts, as disclosed in WO 04/080980,WO 04/056786, WO 03/024967, WO 01/064655, WO 00/053595, and WO01/014402.

Example suitable CDK4/6 inhibitors include palbociclib, ribociclib,trilaciclib, lerociclib, and abemaciclib, and their pharmaceuticallyacceptable salts. Other example suitable CDK4/6 inhibitors includecompounds, and their pharmaceutically acceptable salts, as disclosed inWO 09/085185, WO 12/129344, WO 11/101409, WO 03/062236, WO 10/075074,and WO 12/061156.

In some embodiments, the compounds of the disclosure can be used incombination with one or more other kinase inhibitors including imatinib,particularly for treating patients resistant to imatinib or other kinaseinhibitors.

In some embodiments, the treatment methods of the disclosure can be usedin combination with a chemotherapeutic in the treatment of cancer, andmay improve the treatment response as compared to the response to thechemotherapeutic agent alone, without exacerbation of its toxic effects.In some embodiments, the treatment methods of the disclosure can be usedin combination with a chemotherapeutic provided herein. For example,additional pharmaceutical agents used in the treatment of multiplemyeloma, can include, without limitation, melphalan, melphalan plusprednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib).Further additional agents used in the treatment of multiple myelomainclude Bcr-Abl, Flt-3, RAF and FAK kinase inhibitors. In someembodiments, the agent is an alkylating agent, a proteasome inhibitor, acorticosteroid, or an immunomodulatory agent. Examples of an alkylatingagent include cyclophosphamide (CY), melphalan (MEL), and bendamustine.In some embodiments, the proteasome inhibitor is carfilzomib. In someembodiments, the corticosteroid is dexamethasone (DEX). In someembodiments, the immunomodulatory agent is lenalidomide (LEN) orpomalidomide (POM). Additive or synergistic effects are desirableoutcomes of combining treatment methods of the present disclosure withan additional agent.

The agents can be combined with Compound 1 and/or antibody that binds tohuman PD-1 or human PD-L1, or antigen-binding fragment thereof, of thepresent treatment methods in a single or continuous dosage form, or theagents can be administered simultaneously or sequentially as separatedosage forms.

In some embodiments, a corticosteroid such as dexamethasone isadministered to a patient in combination with the treatment methods ofthe disclosure where the dexamethasone is administered intermittently asopposed to continuously.

The treatment methods described herein can be combined with anotherimmunogenic agent, such as cancerous cells, purified tumor antigens(including recombinant proteins, peptides, and carbohydrate molecules),cells, and cells transfected with genes encoding immune stimulatingcytokines. Non-limiting examples of tumor vaccines that can be usedinclude peptides of melanoma antigens, such as peptides of gp100, MAGEantigens, Trp-2, MARTI and/or tyrosinase, or tumor cells transfected toexpress the cytokine GM-CSF.

The treatment methods described herein can be used in combination with avaccination protocol for the treatment of cancer. In some embodiments,the tumor cells are transduced to express GM-CSF. In some embodiments,tumor vaccines include the proteins from viruses implicated in humancancers such as Human Papilloma Viruses (HPV), Hepatitis Viruses (HBVand HCV) and Kaposi's Herpes Sarcoma Virus (KHSV). In some embodiments,the treatment methods and regimens of the present disclosure can be usedin combination with tumor specific antigen such as heat shock proteinsisolated from tumor tissue itself In some embodiments, the treatmentmethods described herein can be combined with dendritic cellsimmunization to activate potent anti-tumor responses.

The treatment methods and regimens of the present disclosure can be usedin combination with bispecific macrocyclic peptides that target Fe alphaor Fe gamma receptor-expressing effectors cells to tumor cells. Thetreatment methods and regimens of the present disclosure can also becombined with macrocyclic peptides that activate host immuneresponsiveness.

In some further embodiments, the treatment methods of the disclosure arecombined with administration of other therapeutic agents to a patientprior to, during, and/or after a bone marrow transplant or stem celltransplant. The treatment methods and regimens of the present disclosurecan be used in combination with bone marrow transplant for the treatmentof a variety of tumors of hematopoietic origin.

In some embodiments, the compounds described herein can be used incombination with one or more agents for the treatment of diseases suchas cancer. In some embodiments, the agent is an alkylating agent, aproteasome inhibitor, a corticosteroid, or an immunomodulatory agent.Examples of an alkylating agent include cyclophosphamide (CY), melphalan(MEL), and bendamustine. In some embodiments, the proteasome inhibitoris carfilzomib. In some embodiments, the corticosteroid is dexamethasone(DEX). In some embodiments, the immunomodulatory agent is lenalidomide(LEN) or pomalidomide (POM).

Suitable antiviral agents contemplated for use in combination withcompounds of the present disclosure can comprise nucleoside andnucleotide reverse transcriptase inhibitors (NRTIs), non-nucleosidereverse transcriptase inhibitors (NNRTIs), protease inhibitors and otherantiviral drugs.

Example suitable NRTIs include zidovudine (AZT); didanosine (ddl);zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir(1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194);BCH-10652; emitricitabine [(−)-FTC]; beta-L-FD4 (also called beta-L-D4Cand named beta-L-2′,3′-dicleoxy-5-fluoro-cytidene); DAPD,((−)-beta-D-2,6,-diamino-purine dioxolane); and lodenosine (FddA).Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine(BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442(1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione);and (+)-calanolide A (NSC-675451) and B. Typical suitable proteaseinhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538);indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir(BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1 549. Otherantiviral agents include hydroxyurea, ribavirin, IL-2, IL-12,pentafuside and Yissum Project No.11607.

Suitable agents for use in combination with compounds described hereinfor the treatment of cancer include chemotherapeutic agents, targetedcancer therapies, immunotherapies or radiation therapy. Compoundsdescribed herein may be effective in combination with anti-hormonalagents for treatment of breast cancer and other tumors. Suitableexamples are anti-estrogen agents including but not limited to tamoxifenand toremifene, aromatase inhibitors including but not limited toletrozole, anastrozole, and exemestane, adrenocorticosteroids (e.g.prednisone), progestins (e.g. megastrol acetate), and estrogen receptorantagonists (e.g. fulvestrant). Suitable anti-hormone agents used fortreatment of prostate and other cancers may also be combined withcompounds described herein. These include anti-androgens including butnot limited to flutamide, bicalutamide, and nilutamide, luteinizinghormone-releasing hormone (LHRH) analogs including leuprolide,goserelin, triptorelin, and histrelin, LHRH antagonists (e.g.degarelix), androgen receptor blockers (e.g. enzalutamide) and agentsthat inhibit androgen production (e.g. abiraterone).

The compounds described herein may be combined with or in sequence withother agents against membrane receptor kinases especially for patientswho have developed primary or acquired resistance to the targetedtherapy. These therapeutic agents include inhibitors or antibodiesagainst EGFR, Her2, VEGFR, c-Met, Ret, IGFR1, or Flt-3 and againstcancer-associated fusion protein kinases such as Bcr-Abl and EML4-Alk.Inhibitors against EGFR include gefitinib and erlotinib, and inhibitorsagainst EGFR/Her2 include but are not limited to dacomitinib, afatinib,lapitinib and neratinib. Antibodies against the EGFR include but are notlimited to cetuximab, panitumumab and necitumumab. Inhibitors of c-Metmay be used in combination with FGFR inhibitors. These includeonartumzumab, tivantnib, and INC-280. Agents against Abl (or Bcr-Abl)include imatinib, dasatinib, nilotinib, and ponatinib and those againstAlk (or EML4-ALK) include crizotinib.

Angiogenesis inhibitors may be efficacious in some tumors in combinationwith FGFR inhibitors. These include antibodies against VEGF or VEGFR orkinase inhibitors of VEGFR. Antibodies or other therapeutic proteinsagainst VEGF include bevacizumab and aflibercept. Inhibitors of VEGFRkinases and other anti-angiogenesis inhibitors include but are notlimited to sunitinib, sorafenib, axitinib, cediranib, pazopanib,regorafenib, brivanib, and vandetanib

Activation of intracellular signaling pathways is frequent in cancer,and agents targeting components of these pathways have been combinedwith receptor targeting agents to enhance efficacy and reduceresistance. Examples of agents that may be combined with compoundsdescribed herein include inhibitors of the PI3K-AKT-mTOR pathway,inhibitors of the Raf-MAPK pathway, inhibitors of JAK-STAT pathway, andinhibitors of protein chaperones and cell cycle progression.

Agents against the PI3 kinase include but are not limited topilaralisib,idelalisib, buparlisib. Inhibitors of mTOR such as rapamycin, sirolimus,temsirolimus, and everolimus may be combined with FGFR inhibitors. Othersuitable examples include but are not limited to vemurafenib anddabrafenib (Raf inhibitors) and trametinib, selumetinib and GDC-0973(MEK inhibitors). Inhibitors of one or more JAKs (e.g., ruxolitinib,baricitinib, tofacitinib), Hsp90 (e.g., tanespimycin), cyclin dependentkinases (e.g., palbociclib), HDACs (e.g., panobinostat), PARP (e.g.,olaparib), and proteasomes (e.g., bortezomib, carfilzomib) can also becombined with compounds described herein. In some embodiments, the JAKinhibitor is selective for JAK1 over JAK2 and JAK3.

Other suitable agents for use in combination with compounds describedherein include chemotherapy combinations such as platinum-based doubletsused in lung cancer and other solid tumors (cisplatin or carboplatinplus gemcitabine; cisplatin or carboplatin plus docetaxel; cisplatin orcarboplatin plus paclitaxel; cisplatin or carboplatin plus pemetrexed)or gemcitabine plus paclitaxel bound particles (Abraxane®).

Suitable chemotherapeutic or other anti-cancer agents include, forexample, alkylating agents (including, without limitation, nitrogenmustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas andtriazenes) such as uracil mustard, chlormethine, cyclophosphamide(Cytoxan™), ifosfamide, melphalan, chlorambucil, pipobroman,triethylene-melamine, triethylenethiophosphoramine, busulfan,carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

Other suitable agents for use in combination with compounds describedherein include steroids including 17 alpha-ethinylestradiol,diethylstilbestrol, testosterone, prednisone, fluoxymesterone,methylprednisolone, methyltestosterone, prednisolone, triamcinolone,chlorotrianisene, hydroxyprogesterone, aminoglutethimide, andmedroxyprogesteroneacetate.

Other suitable agents for use in combination with compounds describedherein include: dacarbazine (DTIC), optionally, along with otherchemotherapy drugs such as carmustine (BCNU) and cisplatin; the“Dartmouth regimen,” which consists of DTIC, BCNU, cisplatin andtamoxifen; a combination of cisplatin, vinblastine, and DTIC; ortemozolomide. Compounds described herein may also be combined withimmunotherapy drugs, including cytokines such as interferon alpha,interleukin 2, and tumor necrosis factor (TNF) in.

Suitable chemotherapeutic or other anti-cancer agents include, forexample, antimetabolites (including, without limitation, folic acidantagonists, pyrimidine analogs, purine analogs and adenosine deaminaseinhibitors) such as methotrexate, 5-fluorouracil, floxuridine,cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate,pentostatine, and gemcitabine.

Suitable chemotherapeutic or other anti-cancer agents further include,for example, certain natural products and their derivatives (forexample, vinca alkaloids, antitumor antibiotics, enzymes, lymphokinesand epipodophyllotoxins) such as vinblastine, vincristine, vindesine,bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin,idarubicin, ara-C, paclitaxel (TAXOL™), mithramycin, deoxycoformycin,mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide,and teniposide.

Other cytotoxic agents include navelbene, CPT-11, anastrazole,letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, anddroloxafine.

Also suitable are cytotoxic agents such as epidophyllotoxin; anantineoplastic enzyme; a topoisomerase inhibitor; procarbazine;mitoxantrone; platinum coordination complexes such as cis-platin andcarboplatin; biological response modifiers; growth inhibitors;antihormonal therapeutic agents; leucovorin; tegafur; and haematopoieticgrowth factors.

Other anti-cancer agent(s) include antibody therapeutics such astrastuzumab (Herceptin), antibodies to costimulatory molecules such asCTLA-4, 4-1BB, PD-L1 and PD-1 antibodies, or antibodies to cytokines(IL-10, TGF-β, etc.).

Other anti-cancer agents also include those that block immune cellmigration such as antagonists to chemokine receptors, including CCR2 andCCR4.

Other anti-cancer agents also include those that augment the immunesystem such as adjuvants or adoptive T cell transfer.

Anti-cancer vaccines include dendritic cells, synthetic peptides, DNAvaccines and recombinant viruses. In some embodiments, tumor vaccinesinclude the proteins from viruses implicated in human cancers such asHuman Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) andKaposi's Herpes Sarcoma Virus (KHSV). Non-limiting examples of tumorvaccines that can be used include peptides of melanoma antigens, such aspeptides of gp100, MAGE antigens, Trp-2, MARTI and/or tyrosinase, ortumor cells transfected to express the cytokine GM-CSF.

The compounds of the present disclosure can be used in combination withbone marrow transplant for the treatment of a variety of tumors ofhematopoietic origin.

In some embodiments, compounds described herein can be used incombination with immune checkpoint inhibitors. Exemplary immunecheckpoint inhibitors include inhibitors against immune checkpointmolecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR,CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3 (e.g., INCAGN2385),TIM3 (e.g., INCB2390), VISTA, PD-1, PD-L1 and PD-L2. In someembodiments, the immune checkpoint molecule is a stimulatory checkpointmolecule selected from CD27, CD28, CD40, ICOS, OX40 (e.g., INCAGN1949),GITR (e.g., INCAGN1876) and CD137. In some embodiments, the immunecheckpoint molecule is an inhibitory checkpoint molecule selected fromA2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, and VISTA.In some embodiments, the compounds provided herein can be used incombination with one or more agents selected from KIR inhibitors, TIGITinhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFRbeta inhibitors.

In some embodiments, the inhibitor of an immune checkpoint molecule is asmall molecule PD-L1 inhibitor. In some embodiments, the small moleculePD-L1 inhibitor has an IC₅₀ less than 1 μM, less than 100 nM, less than10 nM or less than 1 nM in a PD-L1 assay described in US PatentPublication Nos. US 20170107216, US 20170145025, US 20170174671, US20170174679, US 20170320875, US 20170342060, US 20170362253, and US20180016260, each of which is incorporated by reference in its entiretyfor all purposes.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is MGA012, nivolumab,pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001,ipilumimab or AMP-224. In some embodiments, the anti-PD-1 monoclonalantibody is nivolumab or pembrolizumab. In some embodiments, theanti-PD1 antibody is pembrolizumab. In some embodiments, the anti-PD1antibody is nivolumab. In some embodiments, the anti-PD-1 monoclonalantibody is MGA012 (retifanlimab). In some embodiments, the anti-PD1antibody is SHR-1210. Other anti-cancer agent(s) include antibodytherapeutics such as 4-1BB (e.g. urelumab, utomilumab).

In some embodiments, the compounds of the disclosure can be used incombination with INCB086550.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-Ll monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736,MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments,the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab,AGEN1884, or CP-675,206.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016, LAG525, or INCAGN2385.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments,the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments,the anti-GITR antibody is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228,BMS-986156, GWN323, or MEDI1873.

In some embodiments, the inhibitor of an immune checkpoint molecule isan agonist of OX40, e.g., OX40 agonist antibody or OX4OL fusion protein.In some embodiments, the anti-OX40 antibody is MEDI0562, MOXR-0916,PF-04518600, GSK3174998, or BMS-986178. In some embodiments, the OX40Lfusion protein is MEDI6383.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments,the anti-CD20 antibody is obinutuzumab or rituximab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD19, e.g., an anti-CD19 antibody. In some embodiments,the anti-CD19 antibody is tafasitamab.

The compounds of the present disclosure can be used in combination withbispecific antibodies. In some embodiments, one of the domains of thebispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3,CD137, ICOS, CD3 or TGFP receptor. In some embodiments, the compounds ofthe disclosure can be used in combination with one or more metabolicenzyme inhibitors. In some embodiments, the metabolic enzyme inhibitoris an inhibitor of ID01, TDO, or arginase. Examples of IDO1 inhibitorsinclude epacadostat, NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099and LY338196.

Compounds of the present disclosure can be used in combination with oneor more immune checkpoint inhibitors for the treatment of diseases, suchas cancer or infections. Exemplary immune checkpoint inhibitors includeinhibitors against immune checkpoint molecules such as CBL-B, CD20,CD28, CD40, CD70, CD122, CD96, CD73, CD47, CDK2, GITR, CSF1R, JAK, PI3Kdelta, PI3K gamma, TAM, arginase, HPK1, CD137 (also known as 4-1BB),ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, TLR (TLR7/8), TIGIT,CD112R, VISTA, PD-1, PD-L1 and PD-L2. In some embodiments, the immunecheckpoint molecule is a stimulatory checkpoint molecule selected fromCD27, CD28, CD40, ICOS, OX40, GITR and CD137. In some embodiments, theimmune checkpoint molecule is an inhibitory checkpoint molecule selectedfrom A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3,TIGIT, and VISTA. In some embodiments, the compounds provided herein canbe used in combination with one or more agents selected from KIRinhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4inhibitors and TGFR beta inhibitors.

In some embodiments, the compounds provided herein can be used incombination with one or more agonists of immune checkpoint molecules,e.g., OX40, CD27, GITR, and CD137 (also known as 4-1BB).

In some embodiments, the inhibitor of an immune checkpoint molecule isanti-PD1 antibody, anti-PD-Ll antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1 or PD-L1, e.g., an anti-PD-1 or anti-PD-Llmonoclonal antibody. In some embodiments, the anti-PD-1 or anti-PD-Llantibody is nivolumab, pembrolizumab, atezolizumab, durvalumab,avelumab, cemiplimab, atezolizumab, avelumab, tislelizumab,spartalizumab (PDR001), cetrelimab (JNJ-63723283), toripalimab (JS001),camrelizumab (SHR-1210), sintilimab (IBI308), AB122 (GLS-010), AMP-224,AMP-514/MEDI-0680, BMS936559, JTX-4014, BGB-108, SHR-1210, MEDI4736,FAZ053, BCD-100, KN035, CS1001, BAT1306, LZM009, AK105, HLX10, SHR-1316,CBT-502 (TQB2450), A167 (KL-A167), STI-A101 (ZKAB001), CK-301, BGB-A333,MSB-2311, HLX20, TSR-042, or LY3300054. In some embodiments, theinhibitor of PD-1 or PD-L1 is one disclosed in U.S. Pat. Nos. 7,488,802,7,943,743, 8,008,449, 8,168,757, 8,217,149, or 10,308,644; U.S. Publ.Nos. 2017/0145025, 2017/0174671, 2017/0174679, 2017/0320875,2017/0342060, 2017/0362253, 2018/0016260, 2018/0057486, 2018/0177784,2018/0177870, 2018/0179179, 2018/0179201, 2018/0179202, 2018/0273519,2019/0040082, 2019/0062345, 2019/0071439, 2019/0127467, 2019/0144439,2019/0202824, 2019/0225601, 2019/0300524, or 2019/0345170; or PCT Pub.Nos. WO 03042402, WO 2008156712, WO 2010089411, WO 2010036959, WO2011066342, WO 2011159877, WO 2011082400, or WO 2011161699, which areeach incorporated herein by reference in their entirety. In someembodiments, the inhibitor of PD-L1 is INCB086550.

In some embodiments, the antibody is an anti-PD-1 antibody, e.g., ananti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1antibody is nivolumab, pembrolizumab, cemiplimab, spartalizumab,camrelizumab, cetrelimab, toripalimab, sintilimab, AB122, AMP-224,JTX-4014, BGB-108, BCD-100, BAT1306, LZM009, AK105, HLX10, or TSR-042.In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab,cemiplimab, spartalizumab, camrelizumab, cetrelimab, toripalimab, orsintilimab. In some embodiments, the anti-PD-1 antibody ispembrolizumab. In some embodiments, the anti-PD-1 antibody is nivolumab.In some embodiments, the anti-PD-1 antibody is cemiplimab. In someembodiments, the anti-PD-1 antibody is spartalizumab. In someembodiments, the anti-PD-1 antibody is camrelizumab. In someembodiments, the anti-PD-1 antibody is cetrelimab. In some embodiments,the anti-PD-1 antibody is toripalimab. In some embodiments, theanti-PD-1 antibody is sintilimab. In some embodiments, the anti-PD-1antibody is AB122. In some embodiments, the anti-PD-1 antibody isAMP-224. In some embodiments, the anti-PD-1 antibody is JTX-4014. Insome embodiments, the anti-PD-1 antibody is BGB-108. In someembodiments, the anti-PD-1 antibody is BCD-100. In some embodiments, theanti-PD-1 antibody is BAT1306. In some embodiments, the anti-PD-1antibody is LZM009. In some embodiments, the anti-PD-1 antibody isAK105. In some embodiments, the anti-PD-1 antibody is HLX10. In someembodiments, the anti-PD-1 antibody is TSR-042. In some embodiments, theanti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In someembodiments, the anti-PD1 antibody is SHR-1210. Other anti-canceragent(s) include antibody therapeutics such as 4-1BB (e.g., urelumab,utomilumab). In some embodiments, the inhibitor of an immune checkpointmolecule is an inhibitor of PD-L1, e.g., an anti-PD-Ll monoclonalantibody. In some embodiments, the anti-PD-Ll monoclonal antibody isatezolizumab, avelumab, durvalumab, tislelizumab, BMS-935559, MEDI4736,atezolizumab (MPDL3280A;also known as RG7446), avelumab (MSB0010718C),FAZ053, KN035, CS1001, SHR-1316, CBT-502, A167, STI-A101, CK-301,BGB-A333, MSB-2311, HLX20, or LY3300054. In some embodiments, theanti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, ortislelizumab. In some embodiments, the anti-PD-L1 antibody isatezolizumab. In some embodiments, the anti-PD-L1 antibody is avelumab.In some embodiments, the anti-PD-L1 antibody is durvalumab. In someembodiments, the anti-PD-L1 antibody is tislelizumab. In someembodiments, the anti-PD-L1 antibody is BMS-935559. In some embodiments,the anti-PD-L1 antibody is MEDI4736. In some embodiments, the anti-PD-L1antibody is FAZ053. In some embodiments, the anti-PD-L1 antibody isKN035. In some embodiments, the anti-PD-L1 antibody is CS1001. In someembodiments, the anti-PD-L1 antibody is SHR-1316. In some embodiments,the anti-PD-L1 antibody is CBT-502. In some embodiments, the anti-PD-L1antibody is A167. In some embodiments, the anti-PD-L1 antibody isSTI-A101. In some embodiments, the anti-PD-L1 antibody is CK-301. Insome embodiments, the anti-PD-L1 antibody is BGB-A333. In someembodiments, the anti-PD-L1 antibody is MSB-2311. In some embodiments,the anti-PD-L1 antibody is HLX20. In some embodiments, the anti-PD-L1antibody is LY3300054.

In some embodiments, the inhibitor of an immune checkpoint molecule is asmall molecule that binds to PD-L1, or a pharmaceutically acceptablesalt thereof. In some embodiments, the inhibitor of an immune checkpointmolecule is a small molecule that binds to and internalizes PD-L1, or apharmaceutically acceptable salt thereof. In some embodiments, theinhibitor of an immune checkpoint molecule is a compound selected fromthose in US 2018/0179201, US 2018/0179197, US 2018/0179179, US2018/0179202, US 2018/0177784, US 2018/0177870, US Ser. No. 16/369,654(filed Mar. 29, 2019), and US Ser. No. 62/688,164, or a pharmaceuticallyacceptable salt thereof, each of which is incorporated herein byreference in its entirety.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of KIR, TIGIT, LAIR1, CD160, 2B4 and TGFR beta.

In some embodiments, the inhibitor is MCLA-145.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab,AGEN1884, or CP-675,206.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016, LAG525, INCAGN2385, or eftilagimodalpha (IMP321).

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD73. In some embodiments, the inhibitor of CD73 isoleclumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIGIT. In some embodiments, the inhibitor of TIGIT isOMP-31M32.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of VISTA. In some embodiments, the inhibitor of VISTA isJNJ-61610588 or CA-170.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of B7-H3. In some embodiments, the inhibitor of B7-H3 isenoblituzumab, MGD009, or 8H9.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of KIR. In some embodiments, the inhibitor of KIR islirilumab or IPH4102.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of A2aR. In some embodiments, the inhibitor of A2aR isCPI-444.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TGF-beta. In some embodiments, the inhibitor of TGF-betais trabedersen, galusertinib, or M7824.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PI3K-gamma. In some embodiments, the inhibitor ofPI3K-gamma is IPI-549.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD47. In some embodiments, the inhibitor of CD47 isHu5F9-G4 or TTI-621.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD73. In some embodiments, the inhibitor of CD73 isMEDI9447.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD70. In some embodiments, the inhibitor of CD70 iscusatuzumab or BMS-936561.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments,the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments,the anti-CD20 antibody is obinutuzumab or rituximab.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of OX40, CD27, CD28, GITR, ICOS, CD40, TLR7/8, and CD137 (alsoknown as 4-1BB).

In some embodiments, the agonist of CD137 is urelumab. In someembodiments, the agonist of CD137 is utomilumab.

In some embodiments, the agonist of an immune checkpoint molecule is aninhibitor of GITR. In some embodiments, the agonist of GITR is TRX518,MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, MEDI1873, orMEDI6469.In some embodiments, the agonist of an immune checkpointmolecule is an agonist of OX40, e.g., OX40 agonist antibody or OX40Lfusion protein. In some embodiments, the anti-OX40 antibody isINCAGN01949, MEDI0562 (tavolimab), MOXR-0916, PF-04518600, GSK3174998,BMS-986178, or 9B12. In some embodiments, the OX40L fusion protein isMEDI6383.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of CD40. In some embodiments, the agonist of CD40 is CP-870893,ADC-1013, CDX-1140, SEA-CD40, R07009789, JNJ-64457107, APX-005M, or ChiLob 7/4.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of ICOS. In some embodiments, the agonist of ICOS isGSK-3359609, JTX-2011, or MEDI-570.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of CD28. In some embodiments, the agonist of CD28 istheralizumab.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of CD27. In some embodiments, the agonist of CD27 is varlilumab.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of TLR7/8. In some embodiments, the agonist of TLR7/8 isMEDI9197.

The compounds of the present disclosure can be used in combination withbispecific antibodies. In some embodiments, one of the domains of thebispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3,CD137, ICOS, CD3 or TGFP receptor. In some embodiments, the bispecificantibody binds to PD-1 and PD-L1. In some embodiments, the bispecificantibody that binds to PD-1 and PD-L1 is MCLA-136. In some embodiments,the bispecific antibody binds to PD-L1 and CTLA-4. In some embodiments,the bispecific antibody that binds to PD-L1 and CTLA-4 is AK104.

In some embodiments, the compounds of the disclosure can be used incombination with one or more metabolic enzyme inhibitors. In someembodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1,TDO, or arginase. Examples of IDO1 inhibitors include epacadostat,NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099 and LY338196.Inhibitors of arginase inhibitors include INCB1158.

As provided throughout, the additional compounds, inhibitors, agents,etc. can be combined with the present compound in a single or continuousdosage form, or they can be administered simultaneously or sequentiallyas separate dosage forms.

In some embodiments, the compounds described herein can be used incombination with one or more agents for the treatment of diseases suchas cancer. In some embodiments, the agent is an alkylating agent, aproteasome inhibitor, a corticosteroid, or an immunomodulatory agent.Examples of an alkylating agent include cyclophosphamide (CY), melphalan(MEL), and bendamustine. In some embodiments, the proteasome inhibitoris carfilzomib. In some embodiments, the corticosteroid is dexamethasone(DEX). In some embodiments, the immunomodulatory agent is lenalidomide(LEN) or pomalidomide (POM).

Suitable antiviral agents contemplated for use in combination withcompounds of the present disclosure can comprise nucleoside andnucleotide reverse transcriptase inhibitors (NRTIs), non-nucleosidereverse transcriptase inhibitors (NNRTIs), protease inhibitors and otherantiviral drugs.

Example suitable NRTIs include zidovudine (AZT); didanosine (ddl);zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir(1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194);BCH-10652; emitricitabine [(−)-FTC]; beta-L-FD4 (also called beta-L-D4Cand named beta-L-2′,3′-dicleoxy-5-fluoro-cytidene); DAPD,((−)-beta-D-2,6,-diamino-purine dioxolane); and lodenosine (FddA).Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine(BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442(1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione);and (+)-calanolide A (NSC-675451) and B. Typical suitable proteaseinhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538);indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir(BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1 549. Otherantiviral agents include hydroxyurea, ribavirin, IL-2, IL-12,pentafuside and Yissum Project No.11607.

Suitable agents for use in combination with compounds described hereinfor the treatment of cancer include chemotherapeutic agents, targetedcancer therapies, immunotherapies or radiation therapy. Compoundsdescribed herein may be effective in combination with anti-hormonalagents for treatment of breast cancer and other tumors. Suitableexamples are anti-estrogen agents including but not limited to tamoxifenand toremifene, aromatase inhibitors including but not limited toletrozole, anastrozole, and exemestane, adrenocorticosteroids (e.g.

prednisone), progestins (e.g. megastrol acetate), and estrogen receptorantagonists (e.g. fulvestrant). Suitable anti-hormone agents used fortreatment of prostate and other cancers may also be combined withcompounds described herein. These include anti-androgens including butnot limited to flutamide, bicalutamide, and nilutamide, luteinizinghormone-releasing hormone (LHRH) analogs including leuprolide,goserelin, triptorelin, and histrelin, LHRH antagonists (e.g.degarelix), androgen receptor blockers (e.g. enzalutamide) and agentsthat inhibit androgen production (e.g. abiraterone).

The compounds described herein may be combined with or in sequence withother agents against membrane receptor kinases especially for patientswho have developed primary or acquired resistance to the targetedtherapy. These therapeutic agents include inhibitors or antibodiesagainst EGFR, Her2, VEGFR, c-Met, Ret, IGFR1, or Flt-3 and againstcancer-associated fusion protein kinases such as Bcr-Abl and EML4-Alk.Inhibitors against EGFR include gefitinib and erlotinib, and inhibitorsagainst EGFR/Her2 include but are not limited to dacomitinib, afatinib,lapitinib and neratinib. Antibodies against the EGFR include but are notlimited to cetuximab, panitumumab and necitumumab. Inhibitors of c-Metmay be used in combination with FGFR inhibitors. These includeonartumzumab, tivantnib, and INC-280. Agents against Abl (or Bcr-Abl)include imatinib, dasatinib, nilotinib, and ponatinib and those againstAlk (or EML4-ALK) include crizotinib.

Angiogenesis inhibitors may be efficacious in some tumors in combinationwith FGFR inhibitors. These include antibodies against VEGF or VEGFR orkinase inhibitors of VEGFR. Antibodies or other therapeutic proteinsagainst VEGF include bevacizumab and aflibercept. Inhibitors of VEGFRkinases and other anti-angiogenesis inhibitors include but are notlimited to sunitinib, sorafenib, axitinib, cediranib, pazopanib,regorafenib, brivanib, and vandetanib

Activation of intracellular signaling pathways is frequent in cancer,and agents targeting components of these pathways have been combinedwith receptor targeting agents to enhance efficacy and reduceresistance. Examples of agents that may be combined with compoundsdescribed herein include inhibitors of the PI3K-AKT-mTOR pathway,inhibitors of the Raf-MAPK pathway, inhibitors of JAK-STAT pathway, andinhibitors of protein chaperones and cell cycle progression.

Agents against the PI3 kinase include but are not limited topilaralisib,idelalisib, buparlisib. Inhibitors of mTOR such as rapamycin, sirolimus,temsirolimus, and everolimus may be combined with FGFR inhibitors. Othersuitable examples include but are not limited to vemurafenib anddabrafenib (Raf inhibitors) and trametinib, selumetinib and GDC-0973(MEK inhibitors). Inhibitors of one or more JAKs (e.g., ruxolitinib,baricitinib, tofacitinib), Hsp90 (e.g., tanespimycin), cyclin dependentkinases (e.g., palbociclib), HDACs (e.g., panobinostat), PARP (e.g.,olaparib), and proteasomes (e.g., bortezomib, carfilzomib) can also becombined with compounds described herein. In some embodiments, the JAKinhibitor is selective for JAK1 over JAK2 and JAK3.

Other suitable agents for use in combination with compounds describedherein include chemotherapy combinations such as platinum-based doubletsused in lung cancer and other solid tumors (cisplatin or carboplatinplus gemcitabine; cisplatin or carboplatin plus docetaxel; cisplatin orcarboplatin plus paclitaxel; cisplatin or carboplatin plus pemetrexed)or gemcitabine plus paclitaxel bound particles (Abraxane®).

Suitable chemotherapeutic or other anti-cancer agents include, forexample, alkylating agents (including, without limitation, nitrogenmustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas andtriazenes) such as uracil mustard, chlormethine, cyclophosphamide(Cytoxan™), ifosfamide, melphalan, chlorambucil, pipobroman,triethylene-melamine, triethylenethiophosphoramine, busulfan,carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

Other suitable agents for use in combination with compounds describedherein include steroids including 17 alpha-ethinylestradiol,diethylstilbestrol, testosterone, prednisone, fluoxymesterone,methylprednisolone, methyltestosterone, prednisolone, triamcinolone,chlorotrianisene, hydroxyprogesterone, aminoglutethimide, andmedroxyprogesteroneacetate.

Other suitable agents for use in combination with compounds describedherein include: dacarbazine (DTIC), optionally, along with otherchemotherapy drugs such as carmustine (BCNU) and cisplatin; the“Dartmouth regimen,” which consists of DTIC, BCNU, cisplatin andtamoxifen; a combination of cisplatin, vinblastine, and DTIC; ortemozolomide. Compounds described herein may also be combined withimmunotherapy drugs, including cytokines such as interferon alpha,interleukin 2, and tumor necrosis factor (TNF) in.

Suitable chemotherapeutic or other anti-cancer agents include, forexample, antimetabolites (including, without limitation, folic acidantagonists, pyrimidine analogs, purine analogs and adenosine deaminaseinhibitors) such as methotrexate, 5-fluorouracil, floxuridine,cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate,pentostatine, and gemcitabine.

Suitable chemotherapeutic or other anti-cancer agents further include,for example, certain natural products and their derivatives (forexample, vinca alkaloids, antitumor antibiotics, enzymes, lymphokinesand epipodophyllotoxins) such as vinblastine, vincristine, vindesine,bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin,idarubicin, ara-C, paclitaxel (TAXOL™), mithramycin, deoxycoformycin,mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide,and teniposide.

Other cytotoxic agents include navelbene, CPT-11, anastrazole,letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, anddroloxafine.

Also suitable are cytotoxic agents such as epidophyllotoxin; anantineoplastic enzyme; a topoisomerase inhibitor; procarbazine;mitoxantrone; platinum coordination complexes such as cis-platin andcarboplatin; biological response modifiers; growth inhibitors;antihormonal therapeutic agents; leucovorin; tegafur; and haematopoieticgrowth factors.

Other anti-cancer agent(s) include antibody therapeutics such astrastuzumab (Herceptin), antibodies to costimulatory molecules such asCTLA-4, 4-1BB, PD-L1 and PD-1 antibodies, or antibodies to cytokines(IL-10, TGF-β, etc.).

Other anti-cancer agents also include those that block immune cellmigration such as antagonists to chemokine receptors, including CCR2 andCCR4.

Other anti-cancer agents also include those that augment the immunesystem such as adjuvants or adoptive T cell transfer.

Anti-cancer vaccines include dendritic cells, synthetic peptides, DNAvaccines and recombinant viruses. In some embodiments, tumor vaccinesinclude the proteins from viruses implicated in human cancers such asHuman Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) andKaposi's Herpes Sarcoma Virus (KHSV). Non-limiting examples of tumorvaccines that can be used include peptides of melanoma antigens, such aspeptides of gp100, MAGE antigens, Trp-2, MARTI and/or tyrosinase, ortumor cells transfected to express the cytokine GM-CSF.

The compounds of the present disclosure can be used in combination withbone marrow transplant for the treatment of a variety of tumors ofhematopoietic origin.

Methods for the safe and effective administration of most of thesechemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR, e.g., 1996edition, Medical Economics Company, Montvale, N.J.), the disclosure ofwhich is incorporated herein by reference as if set forth in itsentirety.

As provided throughout, the additional compounds, inhibitors, agents,etc. can be combined with the present compound in a single or continuousdosage form, or they can be administered simultaneously or sequentiallyas separate dosage forms.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, compounds described herein can beadministered in the form of pharmaceutical compositions which refers toa combination of one or more compounds described herein, and at leastone pharmaceutically acceptable carrier or excipient. These compositionscan be prepared in a manner well known in the pharmaceutical art, andcan be administered by a variety of routes, depending upon whether localor systemic treatment is desired and upon the area to be treated.Administration may be topical (including ophthalmic and to mucousmembranes including intranasal, vaginal and rectal delivery), pulmonary(e.g., by inhalation or insufflation of powders or aerosols, includingby nebulizer; intratracheal, intranasal, epidermal and transdermal),ocular, oral or parenteral. Methods for ocular delivery can includetopical administration (eye drops), subconjunctival, periocular orintravitreal injection or introduction by balloon catheter or ophthalmicinserts surgically placed in the conjunctival sac. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal, or intramuscular injection or infusion; orintracranial, e.g., intrathecal or intraventricular, administration.Parenteral administration can be in the form of a single bolus dose, ormay be, for example, by a continuous perfusion pump. Pharmaceuticalcompositions and formulations for topical administration may includetransdermal patches, ointments, lotions, creams, gels, drops,suppositories, sprays, liquids and powders. Conventional pharmaceuticalcarriers, aqueous, powder or oily bases, thickeners and the like may benecessary or desirable.

This disclosure also includes pharmaceutical compositions which contain,as the active ingredient, one or more compounds described herein incombination with one or more pharmaceutically acceptable carriers orexcipients. In making the compositions described herein, the activeingredient is typically mixed with an excipient, diluted by an excipientor enclosed within such a carrier in the form of, for example, acapsule, sachet, paper, or other container. When the excipient serves asa diluent, it can be a solid, semi-solid, or liquid material, which actsas a vehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing, forexample, up to 10% by weight of the active compound, soft and hardgelatin capsules, suppositories, sterile injectable solutions, andsterile packaged powders. In some embodiments, the composition issuitable for topical administration.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art see, e.g., WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions described herein can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

In some embodiments, the pharmaceutical composition comprises silicifiedmicrocrystalline cellulose (SMCC) and at least one compound describedherein, or a pharmaceutically acceptable salt thereof. In someembodiments, the silicified microcrystalline cellulose comprises about98% microcrystalline cellulose and about 2% silicon dioxide w/w.

In some embodiments, the composition is a sustained release compositioncomprising at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier or excipient. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and at least one component selected from microcrystallinecellulose, lactose monohydrate, hydroxypropyl methylcellulose andpolyethylene oxide. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and microcrystalline cellulose, lactose monohydrate andhydroxypropyl methylcellulose. In some embodiments, the compositioncomprises at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and microcrystalline cellulose, lactosemonohydrate and polyethylene oxide. In some embodiments, the compositionfurther comprises magnesium stearate or silicon dioxide. In someembodiments, the microcrystalline cellulose is Avicel PH102™. In someembodiments, the lactose monohydrate is Fast-flo 316™. In someembodiments, the hydroxypropyl methylcellulose is hydroxypropylmethylcellulose 2208 K4M (e.g., Methocel K4 M Premier™) and/orhydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel K00LV™). Insome embodiments, the polyethylene oxide is polyethylene oxide WSR 1105(e.g., Polyox WSR 1105™).

In some embodiments, a wet granulation process is used to produce thecomposition. In some embodiments, a dry granulation process is used toproduce the composition.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 100 mg, more usually about 10 to about30 mg, of the active ingredient. In some embodiments, each dosagecontains about 10 mg of the active ingredient. In some embodiments, eachdosage contains about 50 mg of the active ingredient. In someembodiments, each dosage contains about 25 mg of the active ingredient.The term “unit dosage forms” refers to physically discrete unitssuitable as unitary dosages for human subjects and other mammals, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect, in association with asuitable pharmaceutical excipient.

The components used to formulate the pharmaceutical compositions are ofhigh purity and are substantially free of potentially harmfulcontaminants (e.g., at least National Food grade, generally at leastanalytical grade, and more typically at least pharmaceutical grade).Particularly for human consumption, the composition is preferablymanufactured or formulated under Good Manufacturing Practice standardsas defined in the applicable regulations of the U.S. Food and DrugAdministration. For example, suitable formulations may be sterile and/orsubstantially isotonic and/or in full compliance with all GoodManufacturing Practice regulations of the U.S. Food and DrugAdministration.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpre-formulation composition containing a homogeneous mixture of one ormore compounds described herein. When referring to these pre-formulationcompositions as homogeneous, the active ingredient is typicallydispersed evenly throughout the composition so that the composition canbe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules. This solid pre-formulation is thensubdivided into unit dosage forms of the type described above containingfrom, for example, 0.1 to about 500 mg of the active ingredient of thepresent disclosure.

The tablets or pills of the present disclosure can be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action. For example, the tablet or pill can comprise an innerdosage and an outer dosage component, the latter being in the form of anenvelope over the former. The two components can be separated by anenteric layer which serves to resist disintegration in the stomach andpermit the inner component to pass intact into the duodenum or to bedelayed in release. A variety of materials can be used for such entericlayers or coatings, such materials including a number of polymeric acidsand mixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds, or compositions as describedherein can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions in can be nebulized by use of inert gases. Nebulizedsolutions may be breathed directly from the nebulizing device or thenebulizing device can be attached to a face masks tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions can be administered orally or nasally from devices whichdeliver the formulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, e.g., liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.,glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, e.g., glycerol,hydroxyethyl cellulose, and the like. In some embodiments, topicalformulations contain at least about 0.1, at least about 0.25, at leastabout 0.5, at least about 1, at least about 2 or at least about 5 wt %of the compound of the invention. The topical formulations can besuitably packaged in tubes of, e.g., 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present disclosure can varyaccording to, for example, the particular use for which the treatment ismade, the manner of administration of the compound, the health andcondition of the patient, and the judgment of the prescribing physician.The proportion or concentration of the compounds in a pharmaceuticalcomposition can vary depending upon a number of factors includingdosage, chemical characteristics (e.g., hydrophobicity), and the routeof administration. For example, compounds of the present disclosure canbe provided in an aqueous physiological buffer solution containing about0.1 to about 10% w/v of the compound for parenteral administration. Sometypical dose ranges are from about 1 μg/kg to about 1 g/kg of bodyweight per day. In some embodiments, the dose range is from about 0.01mg/kg to about 100 mg/kg of body weight per day. The dosage is likely todepend on such variables as the type and extent of progression of thedisease or disorder, the overall health status of the particularpatient, the relative biological efficacy of the compound selected,formulation of the excipient, and its route of administration. Effectivedoses can be extrapolated from dose-response curves derived from invitro or animal model test systems.

Compounds described herein can also be formulated in combination withone or more additional active ingredients, which can include anypharmaceutical agent such as anti-viral agents, vaccines, antibodies,immune enhancers, immune suppressants, anti-inflammatory agents and thelike.

Labeled Compounds and Assay Methods

Another aspect of the present invention relates to fluorescent dye, spinlabel, heavy metal or radio-labeled compounds of the invention thatwould be useful not only in imaging techniques but also in assays, bothin vitro and in vivo, for localizing and quantitating the FGFR enzyme intissue samples, including human, and for identifying FGFR enzyme ligandsby inhibition binding of a labeled compound. Substitution of one or moreof the atoms of the compounds of the present disclosure can also beuseful in generating differentiated ADME (Adsorption, Distribution,Metabolism and Excretion). Accordingly, the present invention includesFGFR binding assays that contain such labeled or substituted compounds.

The present invention further includes isotopically-labeled compounds ofthe invention. An “isotopically” or “radio-labeled” compound is acompound of the invention where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present invention include but are not limited to ²H(also written as D for deuterium), ³H (also written as T for tritium),¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br,⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. The radionuclide that isincorporated in the instant radio-labeled compounds will depend on thespecific application of that radio-labeled compound. For example, for invitro FGFR enzyme labeling and competition assays, compounds thatincorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, or ³⁵S will generally be most useful.For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br,⁷⁶Br or ⁷⁷Br will generally be most useful. One or more hydrogen atomsin a compound of the present disclosure can be replaced by deuteriumatoms (e.g., one or more hydrogen atoms of a C₁₋₆ alkyl group of Formula(I) can be optionally substituted with deuterium atoms, such as —CD₃being substituted for —CH₃). In some embodiments, alkyl groups inFormula (I) can be perdeuterated.

One or more constituent atoms of the compounds presented herein can bereplaced or substituted with isotopes of the atoms in natural ornon-natural abundance. In some embodiments, the compound includes atleast one deuterium atom. In some embodiments, the compound includes twoor more deuterium atoms. In some embodiments, the compound includes 1-2,1-3, 1-4, 1-5, or 1-6 deuterium atoms. In some embodiments, all of thehydrogen atoms in a compound can be replaced or substituted by deuteriumatoms.

Synthetic methods for including isotopes into organic compounds areknown in the art (Deuterium Labeling in Organic Chemistry by Alan F.Thomas (New York, N.Y., Appleton-Century-Crofts, 1971; The Renaissanceof H/D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and JochenZimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistryof Isotopic Labelling by James R. Hanson, Royal Society of Chemistry,2011). Isotopically labeled compounds can be used in various studiessuch as NMR spectroscopy, metabolism experiments, and/or assays.

Substitution with heavier isotopes, such as deuterium, may affordcertain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances. (seee.g., A. Kerekes et. al. J. Med. Chem. 2011, 54, 201-210; R. Xu et. al.J. Label Compd. Radiopharm. 2015, 58, 308-312). In particular,substitution at one or more metabolism sites may afford one or more ofthe therapeutic advantages.

The radionuclide that is incorporated in the instant radio-labeledcompounds will depend on the specific application of that radio-labeledcompound. For example, for in vitro adenosine receptor labeling andcompetition assays, compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹Ior ³⁵S can be useful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I,¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br can be useful.

It is understood that a “radio-labeled ” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

Synthetic methods for incorporating radio-isotopes into organiccompounds are applicable to compounds of the invention and are wellknown in the art.

The present disclosure can further include synthetic methods forincorporating radio-isotopes into compounds of the disclosure. Syntheticmethods for incorporating radio-isotopes into organic compounds are wellknown in the art, and an ordinary skill in the art will readilyrecognize the methods applicable for the compounds of disclosure.

A radio-labeled compound of the invention can be used in a screeningassay to identify/evaluate compounds. In general terms, a newlysynthesized or identified compound (i.e., test compound) can beevaluated for its ability to reduce binding of the radio-labeledcompound of the invention to the FGFR4 enzyme. Accordingly, the abilityof a test compound to compete with the radio-labeled compound forbinding to the FGFR4 enzyme directly correlates to its binding affinity.

A labeled compound of the invention can be used in a screening assay toidentify and/or evaluate compounds. For example, a newly synthesized oridentified compound (i.e., test compound) which is labeled can beevaluated for its ability to bind an FGFR protein (e.g., FGFR3) bymonitoring its concentration variation when contacting with the FGFR,through tracking of the labeling. For example, a test compound (labeled)can be evaluated for its ability to reduce binding of another compoundwhich is known to bind to a FGFR protein (i.e., standard compound).Accordingly, the ability of a test compound to compete with the standardcompound for binding to the FGFR protein directly correlates to itsbinding affinity. Conversely, in some other screening assays, thestandard compound is labeled and test compounds are unlabeled.Accordingly, the concentration of the labeled standard compound ismonitored in order to evaluate the competition between the standardcompound and the test compound, and the relative binding affinity of thetest compound is thus ascertained.

Kits

The present invention also includes pharmaceutical kits useful, forexample, in the treatment or prevention of FGFR-associated diseases ordisorders (e.g., cancer), obesity, diabetes and other diseases referredto herein which include one or more containers containing apharmaceutical composition comprising a therapeutically effective amountof a compound of the invention. Such kits can further include, ifdesired, one or more of various conventional pharmaceutical kitcomponents, such as, for example, containers with one or morepharmaceutically acceptable carriers, additional containers, etc., aswill be readily apparent to those skilled in the art. Instructions,either as inserts or as labels, indicating quantities of the componentsto be administered, guidelines for administration, and/or guidelines formixing the components, can also be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples were found to be inhibitorsof one or more FGFR's as described below.

EXAMPLES

Experimental procedures for compounds of the invention are providedbelow. All the starting materials are commercially available or readilysynthezied according to procedures known in the art. Preparatory LC-MSpurifications of some of the compounds prepared were performed on Watersmass directed fractionation systems. The basic equipment setup,protocols, and control software for the operation of these systems havebeen described in detail in the literature. See e.g. “Two-Pump At ColumnDilution Configuration for Preparative LC-MS”, K. Blom, J. Combi. Chem.,4, 295 (2002); “Optimizing Preparative LC-MS Configurations and Methodsfor Parallel Synthesis Purification”, K. Blom, R. Sparks, J. Doughty, G.Everlof, T. Haque, A. Combs, J. Combi. Chem., 5, 670 (2003); and“Preparative LC-MS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem.,6, 874-883 (2004). The compounds separated were typically subjected toanalytical liquid chromatography mass spectrometry (LCMS) for puritycheck under the following conditions: Instrument; Agilent 1100 series,LC/MSD, Column: Waters Sunfire™ C₁₈ 5 μm particle size, 2.1×5.0 mm,Buffers: mobile phase A: 0.025% TFA in water and mobile phase B:acetonitrile; gradient 2% to 80% of B in 3 minutes with flow rate 2.0mL/minute.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

pH=2 purifications: Waters Sunfire™ C₁₈ 5 μm particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.1% TFA (trifluoroacetic acid) inwater and mobile phase B: acetonitrile; the flow rate was 30 mL/minute,the separating gradient was optimized for each compound using theCompound Specific Method Optimization protocol as described in theliterature [see “Preparative LCMS Purification: Improved CompoundSpecific Method Optimization”, K. Blom, B. Glass, R. Sparks, A. Combs,J. Comb. Chem., 6, 874-883 (2004)]. Typically, the flow rate used withthe 30×100 mm column was 60 mL/minute.

pH=10 purifications: Waters XBridge C₁₈ 5 μm particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.15% NH₄OH in water and mobilephase B: acetonitrile; the flow rate was 30 mL/minute, the separatinggradient was optimized for each compound using the Compound SpecificMethod Optimization protocol as described in the literature [See“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)]. Typically, the flow rate used with 30×100 mm columnwas 60 mL/minute.

Example 11-(3-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperidin-3-ol

Step 1. 5-Chloro-3-iodo-1H-pyrazolo[4,3-b]pyridine

A solution of 5-chloro-1H-pyrazolo[4,3-b]pyridine (10 g, 65 mmol) in DMF(60 mL) was treated with 1-iodopyrrolidine-2,5-dione (14.6 g, 65 mmol).The reaction was warmed to 80° C. and stirred for 1 h. The reactionmixture was then cooled to r.t., poured into water (300 mL) and stirredfor 10 min. The resulting solid was filtered, collected and was used inthe next step without further purification. LC-MS calculated forC₆H₄ClIN₃ (M+H)⁺: m/z=279.9; found 279.9.

Step 2. 5-Chloro-3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine

A solution of 5-chloro-3-iodo-1H-pyrazolo[4,3-b]pyridine (13g, 46.5mmol) in DMF (60 mL) was treated with 1-(chloromethyl)-4-methoxybenzene(7.60 ml, 55.8 mmol) and K₂CO₃ (7.71 g, 55.8 mmol). The reaction mixturewas stirred at 90° C. for 1 h. The mixture was then cooled to r.t.,diluted with water and extracted with EtOAc three times. The combinedorganic phases were washed with sat. aq. NaCl, dried with Na₂SO₄,filtered and concentrated to dryness. The residue was purified by silicagel chromatography to afford the desired product. LC-MS calculated forC₁₄H₁₂ClIN₃O (M+H)⁺: m/z=400.0; found 400.0.

Step 3.5-Chloro-1-(4-methoxybenzyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

A solution of5-chloro-3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine (18.58 g,46.5 mmol) in 1,4-dioxane (141 mL) and water (14 mL) was treated with1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(9.68 g, 46.5 mmol), potassium phosphate (19.74 g, 93 mmol), and[dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (3.80 g, 4.65 mmol). The reaction mixture wasdegassed (by evacuation and backfilling with nitrogen) and stirred at80° C. for 8 h. The reaction mixture was then cooled to r.t., dilutedwith EtOAc, washed sequentially with water and sat. aq. NaCl, and driedover Na₂SO₄. The organic phases were filtered and concentrated todryness. The residue was purified by silica gel chromatography to affordthe desired product. LC-MS calculated for C₁₈H₁₇ClN₅O (M+H)⁺: m/z=354.1;found 354.1.

Step 4.1-(3-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperidin-3-ol

A solution of5-chloro-1-(4-methoxybenzyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine(20 mg, 0.056 mmol) in 1,4-dioxane (0.5 mL) was treated withpiperidin-3-ol (5.7 mg, 0.057 mmol), Cs₂CO₃ (35.7 mg, 0.11 mmol), andchloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Ruphos-Pd G2, 3.9 mg, 5.65 μmol). The reaction mixture was degassed (byevacuation and backfilling with nitrogen) and stirred at 100° C. for 8h. The reaction mixture was then concentrated and dissolved in 0.5 mL ofTFA. The mixture was heated at 100° C. for 1 h before concentration andpurification by prep-LCMS (XBridge C18 column, eluting with a gradientof acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min).The product was isolated as the TFA salt. LCMS calculated for C₁₅H₁₉N₆O(M+H)⁺: m/z=299.2; found 299.2.

Example 23-(1-Methyl-1H-pyrazol-4-yl)-5-(1-(trifluoromethyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedure described inExample 1, using1-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine instead ofpiperidin-3-ol. The product was isolated as the TFA salt. LC-MScalculated for C₁₇H₁₆N₈F₃ (M+H)⁺: m/z=389.1; found 389.2.

Example 35-(6,7-Dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedure described inExample 1, using 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine instead ofpiperidin-3-ol. The product was isolated as the TFA salt. LC-MScalculated for C₁₆H₁₇N₈ (M+H)⁺: m/z=321.1; found 321.2.

Example 43-Methyl-8-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-3,8-diazabicyclo[3.2.1]octan-2-one

Step 1.8-(1-(4-Methoxybenzyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-3,8-diazabicyclo[3.2.1]octan-2-one

A solution of5-chloro-1-(4-methoxybenzyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine(Example 1, Step 3; 20 mg, 0.056 mmol) in 1,4-dioxane (0.5 mL) wastreated with 3,8-diazabicyclo[3.2.1]octan-2-one (7 mg, 0.057 mmol),Cs₂CO₃ (0.11 mmol), andchloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Ruphos-Pd G2, 3.9 mg, 5.65 μmol). The reaction was degassed (byevacuation and backfilling with nitrogen) and stirred at 100° C. for 8h. The reaction mixture was cooled, concentrated and purified by silicagel chromatography to afford the desired product. LCMS calculated forC₂₄H₂₆N₇O₂(M+H)⁺: m/z=444.2; found 444.2.

Step 2.3-Methyl-8-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-3,8-diazabicyclo[3.2.1]octan-2-one

A solution of8-(1-(4-methoxybenzyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-3,8-diazabicyclo[3.2.1]octan-2-one(10 mg, 0.022 mmol) in DMF (0.5 mL) was treated with NaH (60% dispersionin mineral oil, 1.1 mg, 0.029 mmol) at 0° C. The reaction mixture wasstirred at this temperature for 30 min before MeI (2 μl, 0.029 mmol) wasadded. The mixture was warmed to rt and stirred for another 30 min.After completion, the reaction was diluted with EtOAc and water. Themixture was extracted with EtOAc 2 times. The organic phases werecombined, washed with water and sat. aq. NaCl, dried with Na₂SO₄,filtered and concentrated to dryness. The residue was then dissolved in0.5 mL of TFA and heated at 100° C. for 1 h. The reaction mixture wascooled, concentrated and purified by prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). The product was isolated as the TFA salt. LCMScalculated for C₁₇H₂₀N₇O (M+H)⁺: m/z=338.2; found 338.2.

Example 53-Isopropyl-1-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one

This compound was prepared according to the procedure described inExample 1, using 3-isopropyl-1-methylpiperazin-2-one instead ofpiperidin-3-ol. LC-MS calculated for C₁₈H₂₄N₇O (M+H)⁺: m/z=354.2; found354.2.

Example 63-Ethyl-1-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one

Step 1.4-(1-(4-Methoxybenzyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1-methylpiperazin-2-one

A solution of5-chloro-1-(4-methoxybenzyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine(Example 1, step 3; 1 g, 2.83 mmol) in 1,4-dioxane (10 mL) was treatedwith 1-methylpiperazin-2-one (0.387 g, 3.39 mmol), Cs₂CO₃ (2.3 g, 7.07mmol), andchloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Ruphos-Pd G2, 0.198 g, 0.28 mmol). The reaction was degassed (byevacuation and backfilling with nitrogen) and stirred at 100° C. for 8h. The reaction mixture was cooled, concentrated and purified by silicagel chromatography to afford the desired product. LCMS calculated forC₂₃H₂₆N₇O₂ (M+H)⁺: m/z=432.2; found 432.2.

Step 2.3-Ethyl-1-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one

A solution of4-(1-(4-methoxybenzyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1-methylpiperazin-2-one(20 mg, 0.046 mmol) in THF was treated with LDA (2.0 M THF solution, 46μL, 0.092 mmol) at −78° C. The resulting solution was stirred at thesame temperature for 20 min before ethyl iodide (7 μl, 0.092 mmol) wasadded. The reaction was slowly warmed up to r.t. and stirred foradditional 20 min. After completion, the reaction was treated with sat.aq. NH₄Cl, and extracted with EtOAc. The organic phases were combined,washed with water and sat. aq. NaCl, dried with Na₂SO₄, filtered andconcentrated to dryness. The residue was then dissolved in 0.5 mL of TFAand heated at 100° C. for 1 h. The reaction mixture was concentrated andpurified by prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). Peak1 was obtained as the TFA salt of the titled compound. LCMS calculatedfor C₁₇H₂₂N₇O (M+H)⁺: m/z=340.2; found 340.2.

Example 73,3-Diethyl-1-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one

This compound was prepared according to the procedure described inExample 6. The reaction was purified by prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). Peak 2 was obtained as the TFA salt of thetitled compound. LCMS calculated for C₁₉H₂₆N₇O (M+H)⁺: m/z=368.2; found368.2.

Example 83-Benzyl-1-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one

This compound was prepared according to the procedure described inExample 6, using (bromomethyl)benzene instead of ethyl iodide in step 2.The product was isolated as the TFA salt. LC-MS calculated for C₂₂H₂₄N₇O(M+H)⁺: m/z=402.2; found 402.2.

Example 93-(Cyclopropylmethyl)-1-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one

This compound was prepared according to the procedure described inExample 6, using (iodomethyl)cyclopropane instead of ethyl iodide instep 2. The product was isolated as the TFA salt. LC-MS calculated forC₁₉H₂₄N₇O (M+H)⁺: m/z=366.2; found 366.2.

Example 101-Methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-(tetrahydro-2H-pyran-4-yl)piperazin-2-one

This compound was prepared according to the procedure described inExample 6, using 4-iodotetrahydro-2H-pyran instead of ethyl iodide instep 2. The product was isolated as the TFA salt. LC-MS calculated forC₂₀H₂₆N₇O₂ (M+H)⁺: m/z=396.2; found 396.2.

Example 111-Methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-(pyridin-4-ylmethyl)piperazin-2-one

This compound was prepared according to the procedure described inExample 6, using 4-4-(bromomethyl)pyridine hydrobromide instead of ethyliodide in step 2. The product was isolated as the TFA salt. LC-MScalculated for C₂₁H₂₃N₈O (M+H)⁺: m/z=403.2; found 403.2.

Example 121-Methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-(1-phenylethyl)piperazin-2-one

This compound was prepared according to the procedure described inExample 6, using 4-4 (1-bromoethyl)benzene instead of ethyl iodide instep 2. The product was isolated as the TFA salt. LC-MS calculated forC₂₃H₂₆N₇O (M+H)⁺: m/z=416.2; found 416.2.

Example 133-Cyclopropyl-1-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one

This compound was prepared according to the procedure described inExample 6, using iodocyclopropane instead of ethyl iodide in step 2. Theproduct was isolated as the TFA salt. LC-MS calculated for C₁₈H₂₂N₇O(M+H)⁺: m/z=352.2; found 352.2.

Example 141-Cyclopropyl-3-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one

Step 1.1-Cyclopropyl-4-(1-(4-methoxybenzyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one

A solution of5-chloro-1-(4-methoxybenzyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine(Example 1, step 3; 500 mg, 1.42 mmol) in 1,4-dioxane (5 mL) was treatedwith 1-cyclopropylpiperazin-2-one (237 mg, 1.7 mmol), Cs₂CO₃ (1.15 g,3.5 mmol), andchloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Ruphos-Pd G2, 99 mg,0.14 mmol). The reaction was degassed (byevacuation and backfilling with nitrogen) and stirred at 100° C. for 8h. The reaction mixture was cooled, concentrated and purified by silicagel chromatography to afford the desired product. LCMS calculated forC₂₅H₂₈N₇O₂ (M+H)⁺: m/z=458.2; found 458.2.

Step 2.1-Cyclopropyl-3-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one

A solution of1-cyclopropyl-4-(1-(4-methoxybenzyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one(20 mg, 0.043 mmol) in THF was treated with LDA (2.0 M THF solution, 46μL, 0.092 mmol) at −78° C. The resulting solution was stirred at thistemperature for 20 min before methyl iodide (8 μl, 0.092 mmol) wasadded. The reaction was slowly warmed up to r.t. and stirred foradditional 20 min. After completion, the reaction was treated with sat.aq. NH₄Cl, and extracted with EtOAc. The organic phases were combined,washed with water and sat. aq. NaCl, dried with Na₂SO₄, filtered andconcentrated to dryness. The residue was dissolved in 0.5 mL of TFA andheated at 100° C. for 1 h. The reaction mixture was cooled, concentratedand purified by prep-LCMS (XBridge C18 column, eluting with a gradientof acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min).Peak 1 was obtained as the TFA salt of the titled compound. LCMScalculated for C₁₈H₂₂N₇O (M+H)⁺: m/z=352.2; found 352.2.

Example 151,3,6-Trimethyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one

Step 1.4-(1-(4-Methoxybenzyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1,6-dimethylpiperazin-2-one

A solution of5-chloro-1-(4-methoxybenzyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine(Example 1, step 3; 500 mg, 1.42 mmol) in 1,4-dioxane (5 mL) was treatedwith 1,6-dimethylpiperazin-2-one (237 mg, 1.7 mmol), Cs₂CO₃ (1.15 g, 3.5mmol), andchloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Ruphos-Pd G2, 99 mg,0.14 mmol). The reaction was degassed (byevacuation and backfilling with nitrogen) and stirred at 100° C. for 8h. The reaction mixture was cooled, concentrated and purified by silicagel chromatography to afford the desired product. LCMS calculated forC₂₄H₂₈N₇O₂ (M+H)⁺: m/z=446.2; found 446.2.

Step 2.1,3,6-Trimethyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one

A solution of4-(1-(4-methoxybenzyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1,6-dimethylpiperazin-2-one(20 mg, 0.043 mmol) in THF was treated with LDA (2.0 M THF solution, 46μL, 0.092 mmol) at −78° C. The resulting solution was stirred at thistemperature for 20 min before methyl iodide (8 μl, 0.092 mmol) wasadded. The reaction was slowly warmed up to r.t. and stirred foradditional 20 min. After completion, the reaction was treated with sat.aq. NH₄Cl, and extracted with EtOAc. The organic phases were combined,washed with water and sat. aq. NaCl, dried with Na₂SO₄, filtered andconcentrated to dryness. The residue was dissolved in 0.5 mL of TFA andheated at 100° C. for 1 h. The reaction mixture was cooled, concentratedand purified by prep-LCMS (XBridge C18 column, eluting with a gradientof acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min).The product was isolated as the TFA salt. LCMS calculated for C₁₇H₂₂N₇O(M+H)⁺: m/z=340.2; found 340.2.

Example 163-Isopropyl-1-methyl-4-(3-(1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one

Step 1. 5-Chloro-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine

A solution of 5-chloro-1H-pyrazolo[4,3-b]pyridine (7.1 g, 46.5 mmol) inDMF (60 mL) was treated with 1-(chloromethyl)-4-methoxybenzene (7.60 ml,55.8 mmol) and K₂CO₃ (7.71 g, 55.8 mmol). The reaction mixture wasstirred at 90° C. for 1 h. The reaction mixture was cooled to r.t.,diluted with water and extracted with EtOAc 3 times. The combinedorganic phases were washed with sat. aq. NaCl, dried with Na₂SO₄,filtered and concentrated to dryness. The residue was purified by silicagel chromatography to afford the desired product. LC-MS calculated forC₁₄H₁₃ClN₃O (M+H)⁺: m/z=274.1; found 274.0.

Step 2.3-Isopropyl-4-(1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1-methylpiperazin-2-one

A solution of 5-chloro-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine(387 mg, 1.42 mmol) in 1,4-dioxane (5 mL) was treated with3-isopropyl-1-methylpiperazin-2-one (265 mg, 1.7 mmol), Cs₂CO₃ (1.15 g,3.5 mmol), andchloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Ruphos-Pd G2, 99 mg,0.14 mmol). The reaction was degassed (byevacuation and backfilling with nitrogen) and stirred at 100° C. for 8h. The reaction mixture was cooled, concentrated and purified by silicagel chromatography to afford the desired product. LCMS calculated forC₂₂H₂₈N₅O₂ (M+H)⁺: m/z=394.2; found 394.2.

Step 3.4-(3-Iodo-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-isopropyl-1-methylpiperazin-2-one

3-Isopropyl-4-(1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1-methylpiperazin-2-one(400 mg, 1.01 mmol) was dissolved in 1 mL TFA and heated at 100° C. for1 h. The reaction mixture was then concentrated and treated with sat.aq. NaHCO₃. The mixture was extracted with DCM 3 times, the combinedorganic phases were washed with sat. aq. NaCl and dried over Na₂SO₄. Thesolvent was concentrated and DMF (3 mL) was added to the residuefollowed by N-iodosuccinimide (226 mg, 1.01 mmol). The mixture washeated to 80° C. for 1 h before K₂CO₃ (168 mg, 1.2 mmol) and1-(chloromethyl)-4-methoxybenzene (0.16 ml, 1.21 mmol) were added. Thereaction was heated at the same temperature for 30 min. The reaction wasthen cooled to r.t. and diluted with water. The mixture was extractedwith EtOAc 3 times, the combined organic phases were washed with sat.aq. NaCl, dried with Na₂SO₄, filtered and concentrated to dryness. Theresidue was purified by silica gel chromatography to afford the desiredproduct. LC-MS calculated for C₂₂H₂₇IN₅O₂ (M+H)⁺: m/z=520.1; found520.0.

Step 4.3-Isopropyl-1-methyl-4-(3-(1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one

A solution of4-(3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-isopropyl-1-methylpiperazin-2-one(20 mg, 0.038 mmol) in 1,4-dioxane (0.5 mL) and water (0.1 mL) wastreated with3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyridine(11 mg, 0.04 mmol), potassium phosphate (19 mg, 0.08 mmol), and[dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (4 mg, 0.005 mmol). The reaction was degassed (byevacuation and backfilling with nitrogen) and stirred at 100° C. for 2h. The reaction mixture was then concentrated to dryness. The residuewas dissolved in 0.5 mL of TFA and heated at 100° C. for 1 h. Thisreaction mixture was concentrated and purified by prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min). The product was isolated as the TFAsalt. LCMS calculated for C₂₃H₂₇N₈O (M+H)⁺: m/z=431.2; found 431.2.

Example 173-Isopropyl-1-methyl-4-(3-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one

This compound was prepared according to the procedure described inExample 16, using4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholineinstead of3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyridinein step 4. LC-MS calculated for C₂₃H₃₃N₈O₂ (M+H)⁺: m/z=453.3; found453.3.

Example 184-(3-(3-Fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-isopropyl-1-methylpiperazin-2-one

This compound was prepared according to the procedure described inExample 16, using1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methylpiperazineinstead of3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyridinein step 4. The product was isolated as the TFA salt. LC-MS calculatedfor C₂₅H₃₃N₇OF (M+H)⁺: m/z=466.3; found 466.3.

Example 193-Isopropyl-1-methyl-4-(3-(thieno[3,2-c]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one

This compound was prepared according to the procedure described inExample 16, using2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thieno[3,2-c]pyridineinstead of3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyridinein step 4. The product was isolated as the TFA salt. LC-MS calculatedfor C₂₁H₂₃N₆OS (M+H)⁺: m/z=407.2; found 407.2.

Example 203-Isopropyl-1-methyl-4-(3-(1-methyl-1H-1,2,3-triazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one

Step 1.3-Isopropyl-4-(1-(4-methoxybenzyl)-3-((trimethylsilyl)ethynyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1-methylpiperazin-2-one

A solution of4-(3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-isopropyl-1-methylpiperazin-2-one(Example 16, step 3; 40 mg, 0.076 mmol) in 1,4-dioxane (1 mL) and water(0.1 mL) was treated withtrimethyl((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethynyl)silane(18 mg, 0.08 mmol), potassium phosphate (40 mg, 0.16 mmol), and[dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (8 mg, 0.01 mmol). The reaction was degassed (byevacuation and backfilling with nitrogen) and stirred at 80° C. for 2 h.The reaction mixture was concentrated to dryness. The residue waspurified by silica gel chromatography to afford the desired product.LC-MS calculated for C₂₇H₃₆N₅O₂Si (M+H)⁺: m/z=490.3; found 490.3.

Step 2.3-Isopropyl-1-methyl-4-(3-(1-methyl-1H-1,2,3-triazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one

A solution of3-isopropyl-4-(1-(4-methoxybenzyl)-3-((trimethylsilyl)ethynyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1-methylpiperazin-2-one(30 mg, 0.06 mmol) in water (1 mL) was treated with iodomethane (0.007mL, 0.12 mmol), sodium azide (5.2 mg, 0.08 mmol), copper(I) iodide (2mg, 0.01) and L-(+)-ascorbic acid sodium salt (2 mg, 0.01 mmol). Thereaction was heated at 75° C. for 10 h. The reaction mixture wasextracted with EtOAc, which was then dried over Na₂SO₄. The solvent wasconcentrated and the residue was dissolved in 0.5 mL of TFA and heatedat 100° C. for 1 h. The reaction mixture was cooled, concentrated andpurified by prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). Theproduct was isolated as the TFA salt. LCMS calculated for C₁₇H₂₃N₈O(M+H)⁺: m/z=355.2; found 355.2.

Example 214-(6-Chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1,3-dimethylpiperazin-2-one

Step 1. 6-Bromo-5-chloro-2-methylpyridin-3-amine

NBS (6.51 g, 36.6 mmol) was added to a solution of5-chloro-2-methylpyridin-3-amine (4.97 g, 34.9 mmol) in DMF (349 ml).After stirring at r.t. for 30 min, water was added and precipitatedproduct was collected by filtration and dried overnight in the air. Thecrude product was used in the next step without further purification.LCMS calculated for C₆H₇N₂BrCl (M+H)⁺: m/z=221.0; found 221.0.

Step 2. N-(6-Bromo-5-chloro-2-methylpyridin-3-yl)acetamide

A solution of 6-bromo-5-chloro-2-methylpyridin-3-amine (7.0 g, 31.6mmol) in acetic acid (79 mL) was treated with acetic anhydride (3.73 ml,39.5 mmol). The reaction was stirred at 50° C. for 1 h, water was thenadded and the precipitated product was collected by filtration. It wasused in the next step without further purification. LCMS calculated forC₈H₉N₂BrClO (M+H)⁺: m/z=263.0; found 263.0.

Step 3. 1-(5-Bromo-6-chloro-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-one

A suspension of N-(6-bromo-5-chloro-2-methylpyridin-3-yl)acetamide (7.2g, 27.3 mmol) in toluene (137 ml) was treated with acetic anhydride(7.73 ml, 82 mmol), potassium acetate (3.22 g, 32.8 mmol) and isopentylnitrite (5.87 ml, 43.7 mmol). The reaction mixture was heated at 100° C.for 2 h and then cooled and diluted with EtOAc. The mixture was washedwith sat. aq. NaHCO₃ and brine, and dried over Na₂SO₄. The solvent wasremoved under vacuum to afford the brown solid as the crude productwhich was used directly in next step without purification. LCMScalculated for C₈H₆N₃BrClO (M+H)⁺: m/z=274.0; found 274.0.

Step 4. 5-Bromo-6-chloro-1H-pyrazolo[4,3-b]pyridine

A solution of1-(5-bromo-6-chloro-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-one (7g, 25.5mmol) in THF (31.9 ml) and methanol (31.9 ml) was treated with 1Msolution of sodium hydroxide (38.3 ml, 38.3 mmol). The mixture wasstirred at 50° C. for 1 h. After completion, most of the solvent wasevaporated and 1N HCl (40 mL) was added. The mixture was treated with200 mL of water and a brown solid slowly formed during stirring of thereaction. The crude product was collected by filtration and used in thenext step without further purification. LCMS calculated for C₆H₄N₃BrCl(M+H)⁺: m/z=232.0; found 232.0.

Step 5.5-Bromo-6-chloro-3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine

A solution of 5-bromo-6-chloro-1H-pyrazolo[4,3-b]pyridine (4g, 17.21mmol) in DMF (20 mL) was treated with N-iodosuccinimide (3.87 g, 17.21mmol). The mixture was heated to 80° C. for 1 h and then K₂CO₃ (2.85 g,20.65 mmol) and 1-(chloromethyl)-4-methoxybenzene (2.69 ml, 20.65 mmol)were added. The reaction was heated at the same temperature for 30 min.After completion, the reaction was cooled to r.t. and diluted withwater. The mixture was extracted with EtOAc 3 times, the combinedorganic phases were washed with sat. aq. NaCl, dried with Na₂SO₄,filtered and concentrated to dryness. The residue was purified by silicagel chromatography to afford the desired product. LC-MS calculated forC₁₄H₁₁BrClIN₃O (M+H)⁺: m/z=477.8; found 477.9.

Step 6.5-Bromo-6-chloro-1-(4-methoxybenzyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

A solution of5-bromo-6-chloro-3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine(3 g, 6.27 mmol) in 1,4-dioxane (50 mL) and water (5 mL) was treatedwith1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.304 g, 6.27 mmol), potassium phosphate (2.66 g, 12.54 mmol), anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (0.512 g, 0.627 mmol). The reaction was degassed(by evacuation and backfilling with nitrogen) and stirred at 80° C. for8 h. The reaction mixture was cooled to r.t., diluted with EtOAc, washedsequentially with water and sat. aq. NaCl, and dried over Na₂SO₄. Theorganic phases were filtered and concentrated to dryness. The residuewas purified by silica gel chromatography to afford the desired product.LC-MS calculated for C₁₈H₁₆ClBrN₅O (M+H)⁺: m/z=432.1; found 432.1.

Step 7.4-(6-Chloro-1-(4-methoxybenzyl)-3-(1-methyl-M-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1,3-dimethylpiperazin-2-one

A solution of5-bromo-6-chloro-1-(4-methoxybenzyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine(240 mg, 0.56 mmol) in 1,4-dioxane (5 mL) was treated with1,3-dimethylpiperazin-2-one (70 mg, 0.57 mmol), Cs₂CO₃ (357 mg, 1.1mmol), andchloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Ruphos-Pd G2, 39 mg, 56.5 μmol). The reaction was degassed (byevacuation and backfilling with nitrogen) and stirred at 100° C. for 8h. The reaction mixture was concentrated to dryness. The residue waspurified by silica gel chromatography to afford the desired product.LC-MS calculated for C₂₄H₂₇ClN₇O₂(M+H)⁺: m/z=480.2; found 480.2.

Step 8.4-(6-Chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1,3-dimethylpiperazin-2-one

4-(6-Chloro-1-(4-methoxybenzyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1,3-dimethylpiperazin-2-one(10 mg, 0.02 mmol) was dissolved in 0.5 mL of TFA. The mixture washeated at 100° C. for 1 h and then concentrated and purified byprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). Theproduct was isolated as the TFA salt. LC-MS calculated for C₁₆H₁₉ClN₇O(M+H)⁺: m/z=360.1; found 360.2.

Example 221,3-Dimethyl-4-(6-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one

A solution of4-(6-chloro-1-(4-methoxybenzyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1,3-dimethylpiperazin-2-one(Example 21, step 7; 18 mg, 0.038 mmol) in 1,4-dioxane (0.5 mL) andwater (0.1 mL) was treated with2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (9.4 mg, 0.075 mmol),potassium phosphate (19 mg, 0.08 mmol), andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(4 mg, 0.005 mmol). The reaction was degassed (by evacuation andbackfilling with nitrogen) and stirred at 100° C. for 2 h. The reactionmixture was concentrated to dryness. The residue was dissolved in 0.5 mLof TFA and heated at 100° C. for 1 h. The reaction mixture was cooled,concentrated and purified by prep-LCMS (XBridge C18 column, eluting witha gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). The product was isolated as the TFA salt. LCMS calculated forC₁₇H₂₂N₇O (M+H)⁺: m/z=340.2; found 340.2.

Example 235-(2,4-Dimethyl-3-oxopiperazin-1-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile

A solution of4-(6-chloro-1-(4-methoxybenzyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1,3-dimethylpiperazin-2-one(Example 21, step 7; 18 mg, 0.038 mmol) in 1,4-dioxane (0.5 mL) andwater (0.2 mL) was treated with potassium hexacyanoferrate(II)trihydrate (32 mg, 0.075 mmol), potassium acetate (3.68 mg, 0.038 mmol),and[(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (4 mg, 0.005 mmol). The reaction was degassed (byevacuation and backfilling with nitrogen) and stirred at 100° C. for 2h. The reaction mixture was then concentrated to dryness. The residuewas dissolved in 0.5 mL of TFA and heated at 100° C. for 1 h. Thereaction mixture was cooled, concentrated and purified by prep-LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min). The product wasisolated as the TFA salt. LCMS calculated for C₁₇H₁₉N₈O (M+H)⁺:m/z=351.1; found 351.2.

Example 244-(6-Methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1,3-dimethylpiperazin-2-one

A solution of4-(6-chloro-1-(4-methoxybenzyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1,3-dimethylpiperazin-2-one(Example 21, step 7; 18 mg, 0.038 mmol) in toluene (0.5 mL) and MeOH(0.1 mL) was treated with Cs₂CO₃ (24.44 mg, 0.075 mmol), and[(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (4 mg, 0.005 mmol). The reaction was degassed (byevacuation and backfilling with nitrogen) and stirred at 100° C. for 2h. The reaction mixture was then concentrated to dryness. The residuewas dissolved in 0.5 mL of TFA and heated at 100° C. for 1 h. Thereaction mixture was concentrated and purified by prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min). The product was isolated as the TFAsalt. LCMS calculated for C₁₇H₂₂N₇O₂(M+H)⁺: m/z=356.2; found 356.2.

Example 254-(6-(Furan-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1,3-dimethylpiperazin-2-one

A solution of4-(6-chloro-1-(4-methoxybenzyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1,3-dimethylpiperazin-2-one(Example 21, step 7; 18 mg, 0.038 mmol) in 1,4-dioxane (0.5 mL) andwater (0.1 mL) was treated with2-(furan-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8 mg, 0.04mmol), potassium phosphate (19 mg, 0.08 mmol), andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(4 mg, 0.005 mmol). The reaction was degassed (by evacuation andbackfilling with nitrogen) and stirred at 100° C. for 2 h. The reactionmixture was then concentrated to dryness. The residue was dissolved in0.5 mL of TFA and heated at 100° C. for 1 h. The reaction mixture wasconcentrated and purified by prep-LCMS (XBridge C18 column, eluting witha gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). The product was isolated as the TFA salt. LCMS calculated forC₂₀H₂₂N₇O₂(M+H)⁺: m/z=392.2; found 392.2.

Example 264-(6-Benzyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1,3-dimethylpiperazin-2-one

A solution of4-(6-chloro-1-(4-methoxybenzyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1,3-dimethylpiperazin-2-one(Example 21, step 7; 18 mg, 0.038 mmol) in THF (1 mL) was treated withbenzylzinc(II) bromide (0.5M THF solution, 0.14 mL, 0.07 mmol), Pd(OAc)₂(1.4 mg, 0.005 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl(4 mg, 0.01 mmol). The reaction was degassed (by evacuation andbackfilling with nitrogen) and stirred at 80° C. for 8 h. The reactionmixture was then concentrated to dryness. The residue was dissolved in0.5 mL of TFA and heated at 100° C. for 1 h. The reaction mixture wasconcentrated and purified by prep-LCMS (XBridge C18 column, eluting witha gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). The product was isolated as the TFA salt. LCMS calculated forC₂₃H₂₆N₇O (M+H)⁺: m/z=416.2; found 416.2.

Example A FGFR Enzymatic Assay

The inhibitor potency of the exemplified compounds was measured in anenzyme assay that measures peptide phosphorylation using FRETmeasurements to detect product formation. Inhibitors were seriallydiluted in DMSO and a volume of 0.5 μL was transferred to the wells of a384-well plate. For FGFR3, a 10 μL volume of FGFR3 enzyme (Millipore)diluted in assay buffer (50 mM HEPES, 10 mM MgCl₂, 1 mM EGTA, 0.01%Tween-20, 5 mM DTT, pH 7.5) was added to the plate and pre-incubated fora time between 5-10 minutes and up to 4 hours. Appropriate controls(enzyme blank and enzyme with no inhibitor) were included on the plate.The assay was initiated by the addition of a 10 μL solution containingbiotinylated EQEDEPEGDYFEWLE peptide substrate (SEQ ID NO: 1) and ATP(final concentrations of 500 nM and 140 μM respectively) in assay bufferto the wells. The plate was incubated at 25° C. for 1 hr. The reactionswere ended with the addition of 10 μL/well of quench solution (50 mMTris, 150 mM NaCl, 0.5 mg/mL BSA, pH 7.8; 30 mM EDTA with Perkin ElmerLance Reagents at 3.75 nM Eu-antibody PY20 and 180 nM APC-Streptavidin).The plate was allowed to equilibrate for ˜1 hr before scanning the wellson a PheraStar plate reader (BMG Labtech).

GraphPad prism3 was used to analyze the data. The IC₅₀ values werederived by fitting the data to the equation for a sigmoidaldose-response with a variable slope.Y=Bottom+(Top−Bottom)/(1+10{circumflex over ( )}((LogIC₅₀−X)*HillSlope))where X is the logarithm of concentration and Y is the response.Compounds having an IC₅₀ of 1 μM or less are considered active.

Table 1 provides IC₅₀ data for compounds of the invention assayed in theFGFR Enzymatic Assay after dilution in assay buffer, added to the plateand pre-incubated for 4 hours. The symbol: “+” indicates an IC₅₀ lessthan 10 nM; “++” indicates an IC₅₀ greater than or equal to 10 nM butless than 30 nM; “+++” indicates an IC₅₀ greater than or equal to 30 nMbut less than 200 nM; and “++++” indicates an IC₅₀ greater than or equalto 200 nM.

TABLE 1 Ex. No. FGFR3 IC₅₀ (nM)  1 ++++  2 +  3 ++++  4 +  5 +  6 +  7++  8 ++  9 ++ 10 ++++ 11 ++++ 12 + 13 + 14 ++ 15 + 16 + 17 ++ 18 + 19 +20 +++ 21 ++ 22 +++ 23 +++ 24 +++ 25 +++ 26 +++

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

What is claimed is:
 1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: Cy¹ is selectedfrom: (i) C₆₋₁₀ aryl, (ii) monocyclic 5-6 membered heteroaryl, whereineach monocyclic 5-6 membered heteroaryl has at least one ring-formingcarbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independentlyselected from N, O, and S; and (iii) bicyclic 8-10 membered heteroaryl,wherein each bicyclic 8-10 membered heteroaryl has at least onering-forming carbon atom, and 1, 2, or 3 ring-forming heteroatomsindependently selected from O and S, and optionally 1, 2 or 3ring-forming heteroatoms that are N; wherein the N and S of themonocyclic 5-6 membered heteroaryl and bicyclic 8-10 membered heteroarylof Cy¹ are optionally oxidized; a ring-forming carbon atom of monocyclic5-6 membered heteroaryl and bicyclic 8-10 membered heteroaryl of Cy¹ isoptionally substituted by oxo to form a carbonyl group; and the C₆₋₁₀aryl, monocyclic 5-6 membered heteroaryl, and bicyclic 8-10 memberedheteroaryl of Cy¹ are each optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹⁰, Cy^(A) is selected fromC₃₋₁₂ cycloalkyl and 4-12 membered heterocycloalkyl; wherein each 4-12membered heterocycloalkyl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of 4-12 membered heterocycloalkyl is optionallysubstituted by oxo to form a carbonyl group; wherein when the C₃₋₁₂cycloalkyl and 4-12 membered heterocycloalkyl of Cy^(A) has a fusedaromatic ring attached thereto, the C₃₋₁₂ cycloalkyl and 4-12 memberedheterocycloalkyl is directly attached to the pyrazolopyridine corestructure through a ring-forming atom of the saturated or partiallysaturated ring; and wherein the C₃₋₁₂ cycloalkyl and 4-12 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3 or 4substituents independently selected from R²⁰; R¹ is selected from H, D,halo, CN, C₁₋₆ alkyl, OR^(a) and NR^(c)R^(d); wherein the C₁₋₆ alkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from R^(g); R² is selected from H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,CN, SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), NR^(c7)R^(d7),NR^(c7)C(O)R^(b7), NR^(c7)C(O)OR^(a7), NR^(c7)S(O)R^(b7),NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), S(O)R^(b7),S(O)NR^(c7)R^(d7), S(O)₂R^(b7), and S(O)₂NR^(c7)R^(d7); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R³⁰; each R¹⁰ is independently selected fromC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a1), SR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1),C(═NOR^(a1))R^(b1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹; each R¹¹ is independently selected fromC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, OR³, SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹²; each R¹² isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, 4-7membered heterocycloalkyl, halo, D, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),and S(O)₂NR^(c5)R^(d5); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-7membered heterocycloalkyl, are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g); each R²⁰ isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a2), SR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)R^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2),C(═NOR^(a2))R^(b2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2),and S(O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R²¹; or twoadjacent R²⁰ substituents on the Cy^(A) ring, taken together with theatoms to which they are attached, form a fused 5- or 6-memberedheteroaryl ring, or a fused phenyl ring; wherein each fused 5- or6-membered heteroaryl ring has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein a ring-forming carbon atom of each fused 5- or 6-memberedheteroaryl ring is optionally substituted by oxo to form a carbonylgroup; and wherein the fused 5- or 6-membered heteroaryl ring, and fusedphenyl ring are each optionally substituted with 1, 2, 3 or 4substituents independently selected from R²¹; each R²¹ is independentlyselected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4),and S(O)₂NR^(c4)R^(d4); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R²²; or two R²¹substituents taken together with the carbon atom to which they areattached form a spiro 3-7-membered heterocycloalkyl ring, or a spiroC₃₋₆ cycloalkyl ring; wherein each spiro 3-7-membered heterocycloalkylring has at least one ring-forming carbon atom and 1, 2 or 3ring-forming heteroatoms independently selected from N, O, and S;wherein a ring-forming carbon atom of each spiro 3-7-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the spiro 3-7membered heterocycloalkyl ringand spiro C₃₋₆ cycloalkyl ring are each optionally substituted with 1,2, 3 or 4 substituents independently selected from R²²; each R²² isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, halo, D, CN, OR^(a6), SR^(a6), COR^(b6),C(O)NR^(c6)R^(d6), C(O)OR^(a6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)OR^(a6), NR^(c6)S(O)R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6),and S(O)₂NR^(c6)R^(d6); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl, are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g); each R³⁰ isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, halo, D, CN, OR^(a8), SR^(a8), C(O)R^(b8),C(O)NR^(c8)R^(d8), C(O)OR^(a8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)OR^(a8), NR^(c8)S(O)R^(b8), NR^(c8)S(O)₂R^(b8),NR^(c8)S(O)₂NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8), S(O)₂R^(b8),and S(O)₂NR^(c8)R^(d8); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl, are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g); each R^(a), R^(c)and R^(d) is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g); each R^(a1), R^(c1) andR^(d1) is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹; or any R^(c1) and R^(d1) attached to the same N atom,together with the N atom to which they are attached, form a 4-, 5-, 6-or 7-membered heterocycloalkyl group optionally substituted with 1, 2,3, or 4 substituents independently selected from R¹¹; each R^(b1) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryland 5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl, are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹¹; each R^(e1)is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkylthio, C₁₋₆ alkyl sulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl; each R^(a2), R^(c2) and R^(d2), is independentlyselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryland 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R²¹; or any R^(c2) andR^(d2) attached to the same N atom, together with the N atom to whichthey are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup optionally substituted with 1, 2 or 3 substituents independentlyselected from R²¹; each R^(b2) is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²¹; each R^(e2) is independently selectedfrom H, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylaminosulfonyl, carbamyl, C₁₋₆alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, aminosulfonyl, C₁₋₆alkylaminosulfonyl and di(C₁₋₆ alkyl)aminosulfonyl; each R^(a3), R^(c3)and R^(d3), is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkylC₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹²; or any R^(c3) and R^(d3) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R¹²; each R^(b3) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl; wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl, are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹²; each R^(a4), R^(c4)and R^(d4), is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkylC₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR²²; or any R^(c4) and R^(d4) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R²²; each R^(b4) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl; wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R²²; each R^(a5), R^(c5)and R^(d5), is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g); or any R^(c5) and R^(d5)attached to the same N atom, together with the N atom to which they areattached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g); each R^(b6) is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R^(g); eachR^(a7), R^(c7) and R^(d7), is independently selected from H, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R^(g); each R^(b6) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, andC₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g); each R^(a7), R^(c7), and R^(d7) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl, are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R³⁰; or anyR^(c7) and R^(d7) attached to the same N atom, together with the N atomto which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R³⁰; each R^(b7) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryland 5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl, are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R³⁰; each R^(a8),R^(c8) and R^(d8), is independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g); or any R^(c8) and R^(d8) attached to the same N atom, togetherwith the N atom to which they are attached, form a 4-, 5-, 6- or7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R^(g); each R^(b8) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl; wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g); and each R^(g) isindependently selected from OH, NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₂alkylene, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₃alkoxy-C₁₋₃ alkoxy, HO—C₁₋₃ alkoxy, HO—C₁₋₃ alkyl, cyano-C₁₋₃ alkyl,H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylsulfonylamino,aminosulfonyl, C₁₋₆ alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₆alkylaminocarbonylamino, and di(C₁₋₆ alkyl)aminocarbonylamino.
 2. Thecompound of claim 1, wherein Cy¹ is selected from monocyclic C₆₋₁₀ aryland monocyclic 5-6 membered heteroaryl; wherein each monocyclic 5-6membered heteroaryl has at least one ring-forming carbon atom and 1, 2,3, or 4 ring-forming heteroatoms independently selected from N, O, andS; wherein the N and S are optionally oxidized; wherein a ring-formingcarbon atom of the monocyclic 5-6 membered heteroaryl is optionallysubstituted by oxo to form a carbonyl group; and wherein the monocyclicC₆₋₁₀ aryl and monocyclic 5-6 membered heteroaryl are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR¹⁰.
 3. The compound of claim 1, wherein Cy¹ is selected from phenyl andmonocyclic 5-6 membered heteroaryl having at least one ring-formingcarbon atom and 1, 2, 3 or 4 ring-forming nitrogen atoms; wherein thephenyl and monocyclic 5-6 membered heteroaryl are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR¹⁰.
 4. The compound of claim 1, wherein Cy¹ is selected fromthienopyridinyl, pyrazolyl, triazolyl and phenyl; whereinthienopyridinyl, pyrazolyl, triazolyl and phenyl are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR¹⁰.
 5. The compound of claim 1, wherein Cy¹ is selected from1-methyl-1H-pyrazol-4-yl, 1-methyl-1H-1,2,3-triazol-4-yl,1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl,1-(2-morpholinoethyl)-1H-pyrazol-4-yl,3-fluoro-4-(4-methylpiperazin-1-yl)phenyl, andthieno[3,2-c]pyridin-2-yl.
 6. The compound of claim 1, wherein each R¹⁰is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a1), SR^(a1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1), andNR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹¹.
 7. Thecompound of claim 1, wherein each R¹⁰ is independently selected fromC₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, halo, D, CN, OR^(a1), C(O)NR^(c1)R^(d1) andNR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl and 4-10membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹¹.
 8. The compound ofclaim 1, wherein each R¹⁰ is independently selected from C₁₋₆ alkyl,4-10 membered heterocycloalkyl, and halo; wherein said C₁₋₆ alkyl and4-10 membered heterocycloalkyl are each optionally substituted with 1,2, 3, or 4 substituents independently selected from R¹¹.
 9. The compoundof claim 1, wherein each R¹⁰ is independently selected from methyl,4-methylpiperazin-1-yl, 2-morpholinoethyl, pyridin-3-ylmethyl andfluoro.
 10. The compound of claim 1, wherein each R¹⁰ is methyl.
 11. Thecompound of claim 1, wherein each R¹¹ is independently selected fromC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), and NR^(c3)R^(d3); wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹².
 12. The compound of claim 1, whereineach R¹¹ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, halo, D, CN, OR^(a3), SR^(a3), and NR^(c3)R^(d3);wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹².
 13. The compound of claim 1, wherein each R¹¹ isindependently selected from 4-10 membered heterocycloalkyl, and 5-10membered heteroaryl.
 14. The compound of claim 1, wherein each R¹¹ isindependently selected from 2-morpholino and pyridin-3-yl.
 15. Thecompound of claim 1, wherein Cy^(A) is 4-12 membered heterocycloalkyl;wherein the 4-12 membered heterocycloalkyl has at least one ring-formingcarbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independentlyselected from N, O, and S; wherein the N and S are optionally oxidized;wherein a ring-forming carbon atom of 4-12 membered heterocycloalkyl isoptionally substituted by oxo to form a carbonyl group; and wherein the4-12 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or4 substituents independently selected from R²⁰.
 16. The compound ofclaim 1, wherein Cy^(A) is 6 membered heterocycloalkyl; wherein the 6membered heterocycloalkyl has at least one ring-forming carbon atom and1 or 2 ring-forming heteroatoms independently selected from N, O, and S;wherein a ring-forming carbon atom of 6 membered heterocycloalkyl isoptionally substituted by oxo to form a carbonyl group; and wherein the6 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4substituents independently selected from R²⁰.
 17. The compound of claim1, wherein Cy^(A) is 6-membered heterocycloalkyl selected frompiperazinyl, piperidinyl, 5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl and6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl; wherein a ring-formingcarbon atom of the 6-membered heterocycloalkyl is optionally substitutedby oxo to form a carbonyl group; and wherein the 6 memberedheterocycloalkyl is optionally substituted with 1, 2, 3 or 4substituents independently selected from R²⁰.
 18. The compound of claim1, wherein Cy^(A) is 4-methyl-3-oxopiperazin-1-yl optionally substitutedwith 1, 2, or 3 substituents independently selected from R²⁰.
 19. Thecompound of claim 1, wherein Cy^(A) is 4-12 membered heterocycloalkyl,optionally substituted with 1, 2, or 3 substituents independentlyselected from R²⁰; wherein the 4-12 membered heterocycloalkyl has atleast one ring-forming carbon atom and 1, 2 or 3 ring-formingheteroatoms independently selected from N, O, and S; wherein at leastone of the ring-forming heteroatoms is N and wherein the 4-12 memberedheterocycloalkyl is attached to the pyrazolopyridine core structurethrough a ring forming nitrogen atom.
 20. The compound of claim 1,wherein Cy^(A) is 4-12 membered heterocycloalkyl, optionally substitutedwith 1, 2, or 3 substituents independently selected from R²⁰; wherein aring-forming carbon atom of the 4-12 membered heterocycloalkyl issubstituted by oxo to form a carbonyl group.
 21. The compound of claim1, wherein Cy^(A) is selected from 3-hydroxypiperidin-1-yl,6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl,1-(trifluoromethyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl,3-methyl-2-oxo-3,8-diazabicyclo[3.2.1]octan-8-yl,2-isopropyl-4-methyl-3-oxopiperazin-1-yl,2-ethyl-4-methyl-3-oxopiperazin-1-yl,2,2-diethyl-4-methyl-3-oxopiperazin-1-yl,2-benzyl-4-methyl-3-oxopiperazin-1-yl,2-(cyclopropylmethyl)-4-methyl-3-oxopiperazin-1-yl,4-methyl-3-oxo-2-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl,4-methyl-3-oxo-2-(pyridin-4-ylmethyl)piperazin-1-yl,4-methyl-3-oxo-2-(1-phenylethyl)piperazin-1-yl,2-cyclopropyl-4-methyl-3-oxopiperazin-1-yl,4-cyclopropyl-2-methyl-3-oxopiperazin-1-yl, and2,4,5-trimethyl-3-oxopiperazin-1-yl.
 22. The compound of claim 1,wherein each R²⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, halo, D,CN, C(O)NR^(c2)R^(d2) and NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₃₋₁₀cycloalkyl and 4-10 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR²¹; or two adjacent R²⁰ substituents on the Cy^(A) ring, taken togetherwith the atoms to which they are attached, form a fused 5- or 6-memberedheteroaryl ring, or a fused phenyl ring; wherein each fused 5- or6-membered heteroaryl ring has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein a ring-forming carbon atom of each fused 5- or 6-memberedheteroaryl ring is optionally substituted by oxo to form a carbonylgroup; and wherein the fused 5- or 6-membered heteroaryl ring, and fusedphenyl ring are each optionally substituted with 1, 2, 3 or 4substituents independently selected from R²¹.
 23. The compound of claim1, wherein each R²⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, andOR^(a2); wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl and 4-10 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R²¹.
 24. The compound of claim1, wherein two adjacent R²⁰ substituents on the Cy^(A) ring, takentogether with the atoms to which they are attached, form a fused 5- or6-membered heteroaryl ring, or a fused phenyl ring; wherein each fused5- or 6-membered heteroaryl ring has at least one ring-forming carbonatom and 1, 2, 3, or 4 ring-forming heteroatoms independently selectedfrom N, O, and S; wherein a ring-forming carbon atom of each fused 5- or6-membered heteroaryl ring is optionally substituted by oxo to form acarbonyl group; and wherein the fused 5- or 6-membered heteroaryl ring,and fused phenyl ring are each optionally substituted with 1, 2, 3 or 4substituents independently selected from R²¹.
 25. The compound of claim1, wherein each R²⁰ is independently selected from OH, methyl, ethyl,isopropyl, cyclopropyl, and tetrahydropyran, each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R²¹; or twoadjacent R²⁰ substituents on the Cy^(A) ring, taken together with theatoms to which they are attached, form a fused pyrazole or imidazole;each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²¹.
 26. The compound of claim 1, whereintwo adjacent R²⁰ substituents on the Cy^(A) ring, taken together withthe atoms to which they are attached, form a fused bicycle such thatCy^(A) is selected from 5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl and6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl; each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR²¹.
 27. The compound of claim 1, wherein each R²¹ is independentlyselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo,D, CN, OR^(a4) and NR^(c4)R^(d4); wherein said C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R²².
 28. The compound of claim1, wherein each R²¹ is independently selected from C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl.
 29. The compoundof claim 1, wherein each R²⁰ is independently selected fromtrifluoromethyl, phenyl, pyridine and cyclopropyl.
 30. The compound ofclaim 1, wherein each R^(a2), R^(c2) and R^(d2), is independentlyselected from H and C₁₋₆ alkyl.
 31. The compound of claim 1, whereineach R is H.
 32. The compound of claim 1, wherein le is selected from H,D, and C₁₋₆ alkyl.
 33. The compound of claim 1, wherein R¹ is H.
 34. Thecompound of claim 1, wherein R² is selected from H, D, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene,4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene,5-10 membered heteroaryl-C₁₋₃ alkylene, halo, CN, OR^(a7), SR^(a7),C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), NR^(c7)R^(d7),NR^(c7)C(O)R^(b7), NR^(c7)C(O)OR^(a7), NR^(c7)S(O)R^(b7),NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), S(O)R^(b7),S(O)NR^(c7)R^(d7), S(O)₂R^(b7), and S(O)₂NR^(c7)R^(d7); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene,4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkyleneand 5-10 membered heteroaryl-C₁₋₃ alkylene are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR³⁰.
 35. The compound of claim 1, wherein R² is selected from H, D, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃alkylene, halo, CN, OR^(a7), and NR^(c7)R^(d7); wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R³⁰.
 36. The compound of claim 1, wherein R²is selected from H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₃alkylene, halo, CN, OR^(a7), and NR^(c7)R^(d7); wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, andC₆₋₁₀ aryl-C₁₋₃ alkylene are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R³⁰.
 37. The compound ofclaim 1, wherein R² is selected from H, methyl, methoxy, chloride,nitrile, furanyl, and benzyl.
 38. The compound of claim 1, wherein R² isH.
 39. The compound of claim 1, wherein each R³⁰ is phenyl.
 40. Thecompound of claim 1, wherein each R^(a7) is methyl.
 41. The compound ofclaim 1, herein the compound is a compound of Formula IIa:

or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, 3, or4.
 42. The compound of claim 1, wherein the compound is a compound ofFormula IIb:

or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, or 3.43. The compound of claim 1, wherein the compound is a compound ofFormula IIc:

or a pharmaceutically acceptable salt thereof, wherein p is 1 or
 2. 44.The compound of claim 1, wherein the compound is a compound of FormulaIId:

or a pharmaceutically acceptable salt thereof, wherein v is 1, 2, 3 or4.
 45. The compound of claim 1, wherein the compound is a compound ofFormula III:

or a pharmaceutically acceptable salt thereof, wherein q is 1, 2, or 3.46. The compound of claim 1, wherein the compound is a compound ofFormula IVa:

or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, 3, or4 and q is 1, 2, or
 3. 47. The compound of claim 1, wherein the compoundis a compound of Formula IVb:

or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, or 3and wherein q is 1, 2, or
 3. 48. The compound of claim 1, wherein thecompound is a compound of Formula IVc:

or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2 andwherein q is 1, 2, or
 3. 49. The compound of claim 1, wherein thecompound is a compound of Formula IVd:

or a pharmaceutically acceptable salt thereof, wherein v is 1, 2, 3 or 4and wherein q is 1, 2, or
 3. 50. The compound of claim 1, wherein: Cy¹is selected from monocyclic C₆₋₁₀ aryl and monocyclic 5-6 memberedheteroaryl; wherein each monocyclic 5-6 membered heteroaryl has at leastone ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein the N and S areoptionally oxidized; wherein a ring-forming carbon atom of themonocyclic 5-6 membered heteroaryl is optionally substituted by oxo toform a carbonyl group; and wherein the monocyclic C₆₋₁₀ aryl andmonocyclic 5-6 membered heteroaryl are each optionally substituted with1, 2, 3 or 4 substituents independently selected from R¹⁰; Cy^(A) isselected from 4-12 membered heterocycloalkyl; wherein the 4-12 memberedheterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3,or 4 ring-forming heteroatoms independently selected from N, O, and S;wherein the N and S are optionally oxidized; wherein a ring-formingcarbon atom of 4-12 membered heterocycloalkyl is optionally substitutedby oxo to form a carbonyl group; and wherein the 4-12 memberedheterocycloalkyl is optionally substituted with 1, 2, 3 or 4substituents independently selected from R²⁰; R¹ is selected from H, D,halo, CN, C₁₋₆ alkyl, OR^(a) and NR^(c)R^(d); wherein the C₁₋₆ alkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from R^(g); R² is selected from H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,CN, and OR^(a7); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R³⁰; each R¹⁰ isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a1), SR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), and NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene,4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkyleneand 5-10 membered heteroaryl-C₁₋₃ alkylene are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹¹; each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), andNR^(c3)R^(d3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹²; each R¹² isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, 4-7membered heterocycloalkyl, halo, D, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5) and NR^(c5)C(O)R^(b5);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-7 membered heterocycloalkyl,are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g); each R²⁰ is independently selectedfrom C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, halo, D, CN, OR^(a2), C(O)NR^(c2)R^(d2) andNR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl and 4-10membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R²¹; or two adjacent R²⁰substituents on the Cy^(A) ring, taken together with the atoms to whichthey are attached, form a fused 5- or 6-membered heteroaryl ring, or afused phenyl ring; wherein each fused 5- or 6-membered heteroaryl ringhas at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms independently selected from N, O, and S; wherein aring-forming carbon atom of each fused 5- or 6-membered heteroaryl ringis optionally substituted by oxo to form a carbonyl group; and whereinthe fused 5- or 6-membered heteroaryl ring, and fused phenyl ring areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R²¹; and each R²¹ is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN, OR^(a4) andNR^(c4)R^(d4); wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²²; or two R²¹ substituents taken together with thecarbon atom to which they are attached form a spiro 3-7-memberedheterocycloalkyl ring, or a spiro C₃₋₆ cycloalkyl ring; wherein eachspiro 3-7-membered heterocycloalkyl ring has at least one ring-formingcarbon atom and 1, 2 or 3 ring-forming heteroatoms independentlyselected from N, O, and S; wherein a ring-forming carbon atom of eachspiro 3-7-membered heterocycloalkyl ring is optionally substituted byoxo to form a carbonyl group; and wherein the spiro 3-7memberedheterocycloalkyl ring and spiro C₃₋₆ cycloalkyl ring are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR²².
 51. The compound of claim 1, wherein: Cy¹ is selected from phenyland monocyclic 5-6 membered heteroaryl having at least one ring-formingcarbon atom and 1, 2, 3 or 4 ring-forming nitrogen atoms; wherein thephenyl and monocyclic 5-6 membered heteroaryl are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR¹⁰; Cy^(A) is selected from 6 membered heterocycloalkyl; wherein the 6membered heterocycloalkyl has at least one ring-forming carbon atom and1 or 2 ring-forming heteroatoms independently selected from N, O, and S;wherein a ring-forming carbon atom of 6 membered heterocycloalkyl isoptionally substituted by oxo to form a carbonyl group; and wherein the6 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4substituents independently selected from R²⁰; R¹ is selected from H, D,and C₁₋₆ alkyl; R² is selected from H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₃ alkylene, halo,CN, and ORa⁷; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, and C₆₋₁₀ aryl-C₁₋₃ alkylene are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R³⁰; each R¹⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, halo,D, CN, OR^(a1), C(O)NR^(c1)R^(d1) and NR^(c1)R^(d1); wherein said C₁₋₆alkyl, C₃₋₁₀ cycloalkyl and 4-10 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹; each R¹¹ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, halo, D, CN, OR^(a3), SR^(a3), andNR^(c3)R^(d3); wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹²; each R¹² is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN,OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),NR^(c5)R^(d5) and NR^(c5)C(O)R^(b5); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl and 4-7 membered heterocycloalkyl, are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g); each R²⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, halo, D,CN, OR^(a2), C(O)NR^(c2)R^(d2) and NR^(c2)R^(d2); wherein said C₁₋₆alkyl, C₃₋₁₀ cycloalkyl and 4-10 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²¹; or two adjacent R²⁰ substituents on the Cy^(A) ring,taken together with the atoms to which they are attached, form a fused5- or 6-membered heteroaryl ring; wherein each fused 5- or 6-memberedheteroaryl ring has at least one ring-forming carbon atom and 1, 2, 3,or 4 ring-forming heteroatoms independently selected from N, O, and S;wherein a ring-forming carbon atom of each fused 5- or 6-memberedheteroaryl ring is optionally substituted by oxo to form a carbonylgroup; and wherein the fused 5- or 6-membered heteroaryl ring, isoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R²¹; and each R²¹ is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, and5-10 membered heteroaryl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R²².
 52. The compound ofclaim 1, wherein: Cy¹ is selected from pyrazolyl, triazolyl and phenyl;wherein the pyrazolyl, triazolyl and phenyl are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR¹⁰; Cy^(A) is 4-12 membered heterocycloalkyl; wherein each 4-12membered heterocycloalkyl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of 4-12 membered heterocycloalkyl is optionallysubstituted by oxo to form a carbonyl group; and wherein the 4-12membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4substituents independently selected from R²⁰; R¹ is H; R² is selectedfrom H, D, C₁₋₆ alkyl, 5-10 membered heteroaryl, halo, CN and OR^(a7);wherein said C₁₋₆ alkyl is optionally substituted with 1, 2 or 3substituents independently selected from R³⁰; each R¹⁰ is independentlyselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, halo, D, CN, OR^(a1), C(O)NR^(c1)R^(d1) andNR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl and 4-10membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹¹; each R¹¹ isindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, halo, D, CN, OR^(a3) andNR^(c3)R^(d3); wherein said C₁₋₆ alkyl, 4-10 membered heterocycloalkyland 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R¹²; each R²⁰ isindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, halo, D, CN, OR^(a2),C(O)NR^(c2)R^(d2) and NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₃₋₁₀cycloalkyl and 4-10 membered heterocycloalkyl, are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR²¹; each R²¹ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, halo, D, CN, OR^(a4) and NR^(c4)R^(d4); whereinsaid C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, are each optionally substituted with 1,2, 3, or 4 substituents independently selected from R²²; each R³⁰ isindependently selected from C₁₋₆ alkyl and phenyl; each R^(a2), R^(c2)and R^(d2), is independently selected from H and C₁₋₆ alkyl; and eachR^(a7) is independently selected from H and C₁₋₆ alkyl.
 53. The compoundof claim 1, wherein: Cy¹ is selected from pyrazolyl, triazolyl, phenyland thienopyridinyl; wherein the pyrazolyl; triazolyl and phenyl areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹⁰; Cy^(A) is 4-12 membered heterocycloalkyl; whereineach 4-12 membered heterocycloalkyl has at least one ring-forming carbonatom and 1, 2, 3, or 4 ring-forming heteroatoms independently selectedfrom N, O, and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of 4-12 membered heterocycloalkyl is optionallysubstituted by oxo to form a carbonyl group; and wherein the 4-12membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4substituents independently selected from R²⁰; R¹ is H; R² is selectedfrom H, C₁₋₆ alkyl, 5-10 membered heteroaryl, halo, CN and OMe; whereinsaid C₁₋₆ alkyl is optionally substituted with 1, 2 or 3 substituentsindependently selected from R³⁰; each R¹⁰ is independently selected fromC₁₋₆ alkyl, and 4-10 membered heterocycloalkyl, halo; wherein said C₁₋₆alkyl and 4-10 membered heterocycloalkyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹¹; eachR¹¹ is independently selected from 4-10 membered heterocycloalkyl and5-10 membered heteroaryl; wherein said 4-10 membered heterocycloalkyland 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R¹²; each R²⁰ isindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, and OH; wherein said C₁₋₆alkyl, C₃₋₁₀ cycloalkyl and 4-10 membered heterocycloalkyl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²¹; each R²¹ is independently selected from C₃₋₁₀cycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl; and each R³⁰ isphenyl.
 54. The compound of claim 1, wherein the compound is selectedfrom:1-(3-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperidin-3-ol;3-(1-Methyl-1H-pyrazol-4-yl)-5-(1-(trifluoromethyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)-1H-pyrazolo[4,3-b]pyridine;5-(6,7-Dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine;3-Methyl-8-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-3,8-diazabicyclo[3.2.1]octan-2-one;3-Isopropyl-1-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one;3-Ethyl-1-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one;3,3-Diethyl-1-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one;3-Benzyl-1-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one;3-(Cyclopropylmethyl)-1-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one;1-Methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-(tetrahydro-2H-pyran-4-yl)piperazin-2-one;1-Methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-(pyridin-4-ylmethyl)piperazin-2-one;1-Methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-(1-phenylethyl)piperazin-2-one;3-Cyclopropyl-1-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one;1-Cyclopropyl-3-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one;1,3,6-Trimethyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one;3-Isopropyl-1-methyl-4-(3-(1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one;3-Isopropyl-1-methyl-4-(3-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one;4-(3-(3-Fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-isopropyl-1-methylpiperazin-2-one;3-Isopropyl-1-methyl-4-(3-(thieno[3,2-c]pyridin-2-yl)-1H-pyrazolo[4,3-yl)piperazin-2-one;3-Isopropyl-1-methyl-4-(3-(1-methyl-1H-1,2,3-triazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one;4-(6-Chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1,3-dimethylpiperazin-2-one;1,3-Dimethyl-4-(6-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)piperazin-2-one;5-(2,4-Dimethyl-3-oxopiperazin-1-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile;4-(6-Methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1,3-dimethylpiperazin-2-one;4-(6-(Furan-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1,3-dimethylpiperazin-2-one;and4-(6-Benzyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1,3-dimethylpiperazin-2-one;or a pharmaceutically acceptable salt thereof.
 55. A pharmaceuticalcomposition comprising a compound of claim 1 or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier orexcipient.
 56. A method of inhibiting an FGFR3 enzyme comprisingcontacting said enzyme with a compound of claim 1 or a pharmaceuticallyacceptable salt thereof.
 57. A method of treating cancer in a patientcomprising administering to said patient a therapeutically effectiveamount of a compound of claim 1 or a pharmaceutically acceptable saltthereof.
 58. A method of treating cancer in a patient comprisingadministering to said patient a therapeutically effective amount of acompound of claim 1 or a pharmaceutically acceptable salt thereof, incombination with another therapy or therapeutic agent.
 59. The method ofclaim 57, wherein said cancer is selected from hepatocellular cancer,bladder cancer, breast cancer, cervical cancer, colorectal cancer,endometrial cancer, gastric cancer, head and neck cancer, kidney cancer,liver cancer, lung cancer, ovarian cancer, prostate cancer, esophagealcancer, gall bladder cancer, pancreatic cancer, thyroid cancer, skincancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adultT cell leukemia, B-cell lymphoma, acute myelogenous leukemia, Hodgkin'sor non-Hodgkin's lymphoma, Waldenstrom's Macroglubulinemia, hairy celllymphoma, Burkett's lymphoma, glioblastoma, melanoma, and rhabdosarcoma.60. The method of claim 57, wherein said cancer is selected fromhepatocellular cancer, breast cancer, bladder cancer, colorectal cancer,melanoma, mesothelioma, lung cancer, prostate cancer, pancreatic cancer,testicular cancer, thyroid cancer, squamous cell carcinoma,glioblastoma, neuroblastoma, uterine cancer, and rhabdosarcoma.